Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors

ABSTRACT

A pharmaceutical formulation comprising the compound of formula

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 13/943,049 filed on Jul.16, 2013 which is a continuation of Ser. No. 12/691,784 filed on Jan.22, 2010, which issued as U.S. Pat. No. 8,513,262 on Aug. 20, 2013,which is a continuation of Ser. No. 11/752,582 filed on May 23, 2007,now abandoned, which is a continuation of U.S. Ser. No. 10/342,810 filedon Jan. 15, 2003, now abandoned, which is a continuation of U.S. Ser.No. 09/582,746 filed on Jun. 30, 2000, which issued as U.S. Pat. No.6,727,256 on Apr. 27, 2004 and which was the national phase applicationof international application PCT/EP99/00048, filed Jan. 8, 1999, whichclaims priority to GB9800569, filed Jan. 12, 1998 in the UK, thecontents of which is incorporated herein by reference.

The present invention relates to a series of substituted heteroaromaticcompounds, methods for their preparation, pharmaceutical compositionscontaining them and their use in medicine. In particular, the inventionrelates to quinoline, quinazoline, pyridopyridine and pyridopyrimidinederivatives which exhibit protein tyrosine kinase inhibition.

Protein tyrosine kinases catalyse the phosphorylation of specifictyrosyl residues in various proteins involved in the regulation of cellgrowth and differentiation (A. F. Wilks, Progress in Growth FactorResearch, 1990, 2, 97-111; S. A. Courtneidge, Dev. Supp.l, 1993, 57-64;J. A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R. F. Paulson,Semin. Immunol., 1995, 7(4), 267-277; A. G. Chan, Curr. Opin. Immunol.,1996, 8(3), 394-401). Protein tyrosine kinases can be broadly classifiedas receptor (e.g. EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) ornon-receptor (e.g. c-src, Ick, zap70) kinases. Inappropriate oruncontrolled activation of many of these kinase, i.e. aberrant proteintyrosine kinase activity, for example by over-expression or mutation,has been shown to result in uncontrolled cell growth.

Aberrant activity of protein tyrosine kinases, such as c-erbB-2, c-src,c-met, EGFr and PDGFr have been implicated in human malignancies.Elevated EGFr activity has, for example, been implicated in non-smallcell lung, bladder and head and neck cancers, and increased c-erbB-2activity in breast, ovarian, gastric and pancreatic cancers. Inhibitionof protein tyrosine kinases should therefore provide a treatment fortumours such as those outlined above.

Aberrant protein tyrosine kinase activity has also been implicated in avariety of other disorders: psoriasis, (Dvir et al, J. Cell. Biol; 1991,113, 857-865), fibrosis, atherosclerosis, restenosis, (Buchdunger et al,Proc. Natl. Acad. Sci. USA; 1991, 92, 2258-2262), auto-immune disease,allergy, asthma, transplantation rejection (Klausner and Samelson, Cell;1991, 64, 875-878), inflammation (Berkois, Blood; 1992, 79(9),2446-2454), thrombosis (Salari et al, FEBS; 1990, 263(1), 104-108) andnervous system diseases (Ohmichi et al, Biochemistry, 1992, 31,4034-4039). Inhibitors of the specific protein tyrosine kinases involvedin these diseases eg PDGF-R in restenosis and EGF-R in psoriasis, shouldlead to novel therapies for such disorders. P56Ick and zap 70 areindicated in disease conditions in which T cells are hyperactive e.g.rheumatoid arthritis, autoimmune disease, allergy, asthma and graftrejection. The process of angiogenesis has been associated with a numberof disease states (e.g. tumourogenesis, psoriasis, rheumatoid arthritis)and this has been shown to be controlled through the action of a numberof receptor tyrosine kinases (L. K. Shawver, DDT, 1997, 2(2), 50-63).

It is therefore a general object of the present invention to providecompounds suitable for the treatment of disorders mediated by proteintyrosine kinase activity, and in particular treatment of the abovementioned disorders.

In addition to the treatment of tumours, the present invention envisagesthat other disorders mediated by protein tyrosine kinase activity may betreated effectively by inhibition, including preferential inhibition, ofthe appropriate protein tyrosine kinase activity.

Broad spectrum inhibition of protein tyrosine kinase may not alwaysprovide optimal treatment of, for example tumours, and could in certaincases even be detrimental to subjects since protein tyrosine kinasesprovide an essential role in the normal regulation of cell growth.

It is another object of the present invention to provide compounds whichpreferentially inhibit protein tyrosine kinases, such as EGFr, c-erbB-2,c-erbB-4, c-met, tie-2, PDGFr, c-src, Ick, Zap70, and fyn. There is alsoperceived to be a benefit in the preferential inhibition involving smallgroups of protein tyrosine kinases, for example groups including two ormore of c-erbB-2, c-erbB-4, EGF-R, Ick and zap70.

A further object of the present invention is to provide compounds usefulin the treatment of protein tyrosine kinase related diseases whichminimise undesirable side-effects in the recipient.

The present invention relates to heterocyclic compounds which may beused to treat disorders mediated by protein tyrosine kinases and inparticular have anti-cancer properties. More particularly, the compoundsof the present invention are potent inhibitors of protein tyrosinekinases such as such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr,c-src, Ick, Zap70, and fyn, thereby allowing clinical management ofparticular diseased tissues.

The present invention envisages, in particular, the treatment of humanmalignancies, for example breast, non-small cell lung, ovary, stomach,and pancreatic tumours, especially those driven by EGF-R or erbB-2,using the compounds of the present invention. For example, the inventionincludes compounds which are highly active against the c-erbB-2 proteintyrosine kinase often in preference to the EGF receptor kinase henceallowing treatment of c-erbB-2 driven tumours. However, the inventionalso includes compounds which are highly active against both c-erbB-2and EGF-R receptor kinases hence allowing treatment of a broader rangeof tumours.

The present invention also includes compounds which are active againstIck and/or zap70 receptor kinases; these may also be active againstc-erbB-2 and/or EGF-R receptor kinases. The compounds may be selectivetowards Ick and/or zap70 in comparison to c-erbB-2 and/or EGF-R.

More particularly, the present invention envisages that disordersmediated by protein tyrosine kinase activity may be treated effectivelyby inhibition of the appropriate protein tyrosine kinase activity in arelatively selective manner, thereby minimising potential side effects.

Accordingly, the present invention provides a compound of formula (I)

or a salt or solvate thereof;wherein X is N or CH;Y is CR¹ and V is N;or Y is N and V is CR¹;or Y is CR¹ and V is CR²;or Y is CR² and V is CR¹;R¹ represents a group CH₃SO₂CH₂CH₂NHCH₂—Ar—, wherein Ar is selected fromphenyl, furan, thiophene, pyrrole and thiazole, each of which mayoptionally be substituted by one or two halo, C₁₋₄ alkyl or C₁₋₄ alkoxygroups;R² is selected from the group comprising hydrogen, halo, hydroxy, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino and di[C₁₋₄ alkyl]amino;U represents a phenyl, pyridyl, 3H-imidazolyl, indolyl, isoindolyl,indolinyl, isoindolinyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl,1H-benzimidazolyl, 2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolylgroup, substituted by an R³ group and optionally substituted by at leastone independently selected R⁴ group;R³ is selected from a group comprising benzyl, halo-, dihalo- andtrihalobenzyl, benzoyl, pyridylmethyl, pyridylmethoxy, phenoxy,benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl;or R³ represents trihalomethylbenzyl or trihalomethylbenzyloxy;or R³ represents a group of formula

wherein each R⁵ is independently selected from halogen, C₁₋₄ alkyl andC₁₋₄ alkoxy; and n is 0 to 3;each R⁴ is independently hydroxy, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, di[C₁₋₄ alkyl]amino,C₁₋₄ alkylthio, C₁₋₄ alkylsulphinyl, C₁₋₄ alkylsulphonyl, C₁₋₄alkylcarbonyl, carboxy, carbamoyl, C₁₋₄ alkoxycarbonyl, C₁₋₄alkanoylamino, N—(C₁₋₄ alkyl)carbamoyl, N,N-di(C₁₋₄ alkyl)carbamoyl,cyano, nitro and trifluoromethyl;with the proviso that the following compounds are excluded:

-   (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl-amine;-   (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl-amine;-   (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl-amine;-   (1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl-amine;-   (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-1-methyl-pyrrol-2-yl)-quinazolin-4-yl-amine;    and their hydrochloride salts.

Solvates of the compounds of formula (I) are also included within thescope of the present invention.

The definitions for X, Y and V thus give rise to a number of possiblebasic ring systems for the compounds of formula (I). In particular thecompounds may contain the following basic ring systems:

It will be seen that for compounds containing the basic ring system (1)the group R¹ may be at the 6- or 7-position; the compounds in which R¹is in the 7-position are of particular interest in the context of Ickand/or zap70 activity.

It will be seen that for compounds containing the basic ring system (2)the group R¹ may be at the 6- or 7-position; the compounds in which R¹is in the 6-position are of particular interest in the context ofc-erbB-2 activity whereas the compounds in which R¹ is in the 7-positionare of particular interest in the context of Ick and/or zap70 activity.

Ring systems (1), (2), (5) and (6) are preferred; ring systems (2) and(6) are more preferred.

Ring system (1) is also more preferred.

Alkyl groups containing three or more carbon atoms may be straight,branched or cyclised; preferably they are straight or branched.References to a specific alkyl group such as “butyl” is intended torefer to the straight chain (n-) isomer only. References to othergeneric terms such as alkoxy, alkylamino etc. are to be interpretedanalogously.

Suitable values for the various groups listed above within thedefinitions for R¹, R², R⁴ and R⁵ are as follows:

halo is, for example, fluoro, chloro, bromo or iodo; preferably it isfluoro, chloro or bromo, more preferably fluoro or chloro;

C₁₋₄ alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl or tert-butyl; preferably it is methyl, ethyl,propyl, isopropyl or butyl, more preferably methyl;

C₂₋₄ alkenyl is, for example, ethenyl, prop-1-enyl or prop-2-enyl;preferably it is ethenyl;

C₂₋₄ alkynyl is, for example, ethynyl, prop-1-ynyl or prop-2-ynyl;preferably it is ethynyl;

C₁₋₄ alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; preferably it ismethoxy, ethoxy, propoxy, isopropoxy or butoxy; more preferably it ismethoxy;

C₁₋₄ alkylamino is, for example, methylamino, ethylamino or propylamino;preferably it is methylamino;

di[C₁₋₄ alkyl]amino is, for example, dimethylamino, diethylamino,N-methyl-N-ethylamino or dipropylamino; preferably it is dimethylamino;

C₁₋₄ alkylthio is, for example, methylthio, ethylthio, propylthio orisopropylthio, preferably methylthio;

C₁₋₄ alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl,propylsulphinyl or isopropylsulphinyl, preferably methylsulphinyl;

C₁₋₄ alkylsulphonyl is, for example, methanesulphonyl, ethylsulphonyl,propylsulphonyl or isopropylsulphonyl, preferably methanesulphonyl;

C₁₋₄ alkylcarbonyl is, for example methylcarbonyl, ethylcarbonyl orpropylcarbonyl;

C₁₋₄ alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl or tert-butoxycarbonyl;

C₁₋₄ alkanoylamino (where the number of carbon atoms includes the COfunctionality) is, for example, formamido, acetamido, propionamido orbutyramido;

N—(C₁₋₄ alkyl)carbamoyl is, for example, N-methylcarbamoyl orN-ethylcarbamoyl;

N,N-di(C₁₋₄ alkyl)carbamoyl is, for example, N,N-dimethylcarbamoyl,N-methyl-N-ethylcarbamoyl or N,N-diethylcarbamoyl.

In an especially preferred embodiment X is N, Y is CR¹ and V is CR²(ring system (2) above).

In a further especially preferred embodiment X is N, Y is CR² and V isCR¹ (ring system (2) above).

In a further especially preferred embodiment X is N, Y is CR¹ and V is N(ring system (6) above).

In a preferred embodiment R² represents hydrogen or C₁₋₄ alkoxy.

In a more preferred embodiment R² represents hydrogen or methoxy.

In a further preferred embodiment R² represents halo; more preferred R²is fluoro.

In a preferred embodiment the group Ar is substituted by one halo, C₁₋₄alkyl or C₁₋₄ alkoxy group.

In a more preferred embodiment the group Ar is substituted by a C₁₋₄alkyl group.

In a further more preferred embodiment the group Ar does not carry anyoptional substituents.

In a further more preferred embodiment Ar represents furan, phenyl orthiazole, each of which may optionally be substituted as indicatedabove.

In a further more preferred embodiment Ar represents furan or thiazole,each of which may optionally be substituted as indicated above.

In a most preferred embodiment Ar represents unsubstituted furan orthiazole.

The side chain CH₃SO₂CH₂CH₂NHCH₂ may be linked to any suitable positionof the group Ar. Similarly, the group R¹ may be linked to the carbonatom carrying it from any suitable position of the group Ar.

In a preferred embodiment, when Ar represents furan the side chainCH₃SO₂CH₂CH₂NHCH₂ is in the 4-position of the furan ring and the link tothe carbon atom carrying the group R¹ is from the 2-position of thefuran ring.

In another preferred embodiment, when Ar represents furan the side chainCH₃SO₂CH₂CH₂NHCH₂ is in the 3-position of the furan ring and the link tothe carbon atom carrying the group R¹ is from the 2-position of thefuran ring.

In a most preferred embodiment, when Ar represents furan the side chainCH₃SO₂CH₂CH₂NHCH₂ is in the 5-position of the furan ring and the link tothe carbon atom carrying the group R¹ is from the 2-position of thefuran ring.

In a further most preferred embodiment, when Ar represents thiazole theside chain CH₃SO₂CH₂CH₂NHCH₂ is in the 2-position of the thiazole ringand the link to the carbon atom carrying the group R¹ is from the4-position of the thiazole ring.

The R³ and R⁴ groups may be bound to the ring system U by either acarbon atom or a heteroatom of the ring system. The ring system itselfmay be bound to the bridging NH group by a carbon atom or a heteroatombut is preferably bound by a carbon atom. The R³ and R⁴ groups may bebound to either ring when U represents a bicyclic ring system, but thesegroups are preferably bound to the ring which is not bound to thebridging NH group in such a case.

In a preferred embodiment U represents a phenyl, indolyl, or1H-indazolyl group substituted by an R³ group and optionally substitutedby at least one independently selected R⁴ group.

In a more preferred embodiment U represents a phenyl or 1H-indazolylgroup substituted by an R³ group and optionally substituted by at leastone independently selected R⁴ group.

In a more preferred embodiment, where U represents a phenyl group thegroup R³ is in the para-position relative to the bond from U to thelinking NH group.

In a further more preferred embodiment, where U represents a1H-indazolyl group the group R³ is in the 1-position of the indazolylgroup.

In a preferred embodiment R³ represents benzyl, pyridylmethyl, phenoxy,benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl.

In a further preferred embodiment R³ represents trihalomethylbenzyloxy.

In a further preferred embodiment R³ represents a group of formula

wherein Hal is Br or Cl, particularly Cl, more especially wherein theHal substituent is in the position marked with a star in the ring asshown.

In a more preferred embodiment R³ represents benzyloxy, fluorobenzyloxy(especially 3-fluorobenzyloxy), benzyl, phenoxy and benzenesulphonyl.

In a further more preferred embodiment R³ represents bromobenzyloxy(especially 3-bromobenzyloxy) and trifluoromethylbenzyloxy.

In a further preferred embodiment the ring U is not substituted by an R⁴group; in an especially preferred embodiment U is phenyl or indazolylunsubstituted by an R⁴ group.

In a further preferred embodiment the ring U is substituted by an R⁴group selected from halo or C₁₋₄ alkoxy; especially chloro, fluoro ormethoxy.

In a more preferred embodiment the ring U is substituted by an R⁴ groupwherein R⁴ represents halo, especially 3-fluoro.

In an especially preferred embodiment U together with R⁴ representsmethoxyphenyl, fluorophenyl, trifluoromethylphenyl or chlorophenyl.

In a more especially preferred embodiment U together with R⁴ representsmethoxyphenyl or fluorophenyl.

In an especially preferred embodiment the group U together with thesubstituent(s) R³ and R⁴ represents benzyloxyphenyl,(fluorobenzyloxy)phenyl, (benzenesulphonyl)phenyl, benzylindazolyl orphenoxyphenyl.

In a more especially preferred embodiment the group U together with thesubstituent(s) R³ and R⁴ represents benzyloxyphenyl,(3-fluorobenzyloxy)phenyl, (benzenesulphonyl)phenyl or benzylindazolyl.

In another more especially preferred embodiment the group U togetherwith the substituent(s) R³ and R⁴ represents (3-bromobenzyloxy)phenyl,(3-trifluoromethylbenzyloxy)phenyl, or(3-fluorobenzyloxy)-3-methoxyphenyl.

In another more especially preferred embodiment the group U togetherwith the substituent(s) R³ and R⁴ represents3-fluorobenzyloxy-3-chlorophenyl, benzyloxy-3-chlorophenyl,benzyloxy-3-trifluoromethylphenyl, (benzyloxy)-3-fluorophenyl,(3-fluorobenzyloxy)-3-fluorophenyl or (3-fluorobenzyl)indazolyl.

In a most especially preferred embodiment the group U together with thesubstituent(s) R³ and R⁴ represents benzyloxyphenyl or(3-fluorobenzyloxy)phenyl.

In a preferred embodiment there is provided a compound of formula (I) ora salt or solvate thereof wherein X is N; V is CR², wherein R² ishydrogen, halo (especially fluoro) or C₁₋₄ alkoxy (especially methoxy);Y is CR¹ wherein R¹ is as defined above in which Ar is unsubstitutedphenyl, furan or thiazole; U is phenyl or indazole; R³ is benzyl,fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy,trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R⁴ is notpresent or is halo (especially chloro or fluoro), or methoxy.

In a most preferred embodiment there is provided a compound of formula(I) or a salt or solvate thereof wherein X is N; V is CR², wherein R² ishydrogen, halo (especially fluoro) or C₁₋₄ alkoxy (especially methoxy);Y is CR¹ wherein R¹ is as defined above in which Ar is unsubstitutedfuran or thiazole; U is phenyl; R³ is benzyloxy, fluorobenzyloxy orbenzenesulphonyl; and R⁴ is not present or is halo (especially chloro orfluoro), or methoxy.

In a most preferred embodiment there is provided a compound of formula(I) or a salt or solvate thereof wherein X is N; V is CR², wherein R² ishydrogen, halo (especially fluoro) or C₁₋₄ alkoxy (especially methoxy);Y is CR¹ wherein R¹ is as defined above in which Ar is unsubstitutedfuran or thiazole; U is indazole; R³ is benzyl or fluorobenzyl; and R⁴is not present.

In a further more preferred embodiment there is provided a compound offormula (I) or a salt or solvate thereof wherein X is N; Y is CR²,wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole;R³ is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy,trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R⁴ is notpresent or is halo (especially chloro or fluoro), or methoxy.

In a further most preferred embodiment there is provided a compound offormula (I) or a salt or solvate thereof wherein X is N; Y is CR²,wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is phenyl; R³ is benzyloxy,fluorobenzyloxy or benzenesulphonyl; and R⁴ is not present or is halo(especially chloro or fluoro), or methoxy.

In a further most preferred embodiment there is provided a compound offormula (I) or a salt or solvate thereof wherein X is N; Y is CR²,wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is indazole; R³ is benzyl orfluorobenzyl; and R⁴ is not present.

In a most especially preferred embodiment there is provided a compoundof formula (I) or a salt or solvate thereof wherein X is N, Y is CR²,wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is phenyl; R³ is phenoxy; andR⁴ is not present.

In another more preferred embodiment there is provided a compound offormula (I) or a salt or solvate thereof wherein X is N; V is N; Y isCR¹ wherein R¹ is as defined above in which Ar is unsubstituted phenyl,furan or thiazole; U is phenyl or indazole; R³ is benzyl, fluorobenzyl,benzyloxy, fluorobenzyloxy, bromobenzyloxy, trifluoromethylbenzyloxy,phenoxy or benzenesulphonyl; and R⁴ is not present or is halo(especially chloro or fluoro), or methoxy.

In another most preferred embodiment there is provided a compound offormula (I) or a salt or solvate thereof wherein X is N; V is N, Y isCR¹ wherein R¹ is as defined above in which Ar is unsubstituted furan orthiazole; U is phenyl; R³ is benzyloxy, fluorobenzyloxy orbenzenesulphonyl; and R⁴ is not present or is halo (especially chloro orfluoro), or methoxy.

In another most preferred embodiment there is provided a compound offormula (I) or a salt or solvate thereof wherein X is N; V is N, Y isCR¹ wherein R¹ is as defined above in which Ar is unsubstituted furan orthiazole; U is indazole; R³ is benzyl or fluorobenzyl; and R⁴ is notpresent.

In yet another preferred embodiment there is provided a compound offormula (I) or a salt or solvate thereof wherein X is CH; Y is CR²,wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole;R³ is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy,trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R⁴ is notpresent or is halo (especially chloro or fluoro), or methoxy.

In yet another most preferred embodiment there is provided a compound offormula (I) or a salt or solvate thereof wherein X is CH; Y is CR²,wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is phenyl; R³ is benzyloxy,fluorobenzyloxy, phenoxy or benzenesulphonyl; and R⁴ is not present oris halo (especially chloro or fluoro), or methoxy.

In yet another most preferred embodiment there is provided a compound offormula (I) or a salt or solvate thereof wherein X is CH; Y is CR²,wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is indazole; R³ is benzyl orfluorobenzyl; and R⁴ is not present.

In a most especially preferred embodiment there is provided a compoundof formula (I) or a salt or solvate thereof wherein X is CH, Y is CR²,wherein R² is hydrogen, halo (especially fluoro) or C₁₋₄ alkoxy(especially methoxy); V is CR¹ wherein R¹ is as defined above in whichAr is unsubstituted furan or thiazole; U is phenyl; R³ is phenoxy; andR⁴ is not present.

Preferred compounds of the present invention include:

-   4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-(Benzyloxy)phenyl]-6-[4-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(Benzyloxy)-3-fluorophenyl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine;-   N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-(Benzyloxy)phenyl]-6-[3-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine;-   6-[2-({[2-(Methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine;-   6-[2-({[2-(Methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine-   N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-(1-Benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-(3-Fluoro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-(3-Chloro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-7-methoxy-N-(4-benzenesulphonyl)phenyl-4-quinazolinamine;-   N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-(Benzenesulphonyl)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine;    and salts or solvates thereof, particularly pharmaceutically    acceptable salts thereof.

Other preferred compounds of the present invention include:

-   (4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazol-4-yl)-quinolin-4-yl)amine;-   (4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazol-5-yl)-quinolin-4-yl)amine;-   (4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-2-yl)-quinolin-4-yl)amine;    and salts or solvates thereof, particularly pharmaceutically    acceptable salts thereof.

Other preferred compounds of the present invention include the following(in groups denoted hereafter as Lists 1 to 48):

List 1

-   (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)amine;-   (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;    List 2-   (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;    List 3-   (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;    List 4-   (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;    List 5-   (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;    List 6-   (1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;    List 7-   (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;    List 8-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;    List 9-   (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;    List 10-   (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;    List 11-   (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;    List 12-   (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;    List 13-   (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;    List 14-   (1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)amine;-   (4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;    List 15-   (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;    List 16-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;    List 17-   (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;    List 18-   (1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;    List 19-   (1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;    List 20-   (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;    List 21-   (1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;    List 22-   (1-Benzyl-1H-indazol-5-yl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)amine;-   (4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;    List 23-   (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)quinazolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinazolin-4-yl)-amine;    List 24-   (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;    List 25-   (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;    List 26-   (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;    List 27-   (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;    List 28-   (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;    List 29-   (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine;    List 30-   (1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;    List 31-   (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine;    List 32-   (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;    List 33-   (1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)amine;    List 34-   (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinolin-4-yl)amine;-   (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;    List 35-   (1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;    List 36-   (1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;    List 37-   (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;    List 38-   (1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;    List 39-   (1-Benzyl-1H-indazol-5-yl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)quinolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;    List 40-   (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;-   (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)quinolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine;    List 41-   (4-Benzyloxy-3-chlorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-iodophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-fluorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-fluorophenyl-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;    List 42-   (4-Benzyloxy-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-fluorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-fluorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;    List 43-   (4-Benzyloxy-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine-   (4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;    List 44-   (4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(5-((2methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-3-bromophenyl)-(6-(5-((2methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(5-((2methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Benzyloxy-3-iodophenyl)-(6-(5-((2methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(5-((2methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine.    List 45-   N-[4-(Benzyloxy)-3-chlorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-trifluoromethyl    phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-bromophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-iodophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-fluorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[1-(3-Fluorobenzyl-1H-indazol-5-yl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;    List 46-   N-[4-(Benzyloxy)-3-chlorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine-   N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine-   N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine-   N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine-   N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine-   N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine-   N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine-   N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine-   N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine-   N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine    List 47-   N-[4-(benzyloxy)-3-chlorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4yl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-bromophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-iodophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-fluorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;    List 48-   N-[4-(benzyloxy)-3-chlorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;    and salts or solvates thereof, particularly pharmaceutically    acceptable salts or solvates thereof.

Particularly preferred compounds of the present invention include:

-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxyphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine;-   N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-(1-Benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-(3-Fluoro-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine;-   N-(3-Chloro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine;-   N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine;-   N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine;    and salts or solvates thereof, particularly pharmaceutically    acceptable salts or solvates thereof.

Further particularly preferred compounds of the present inventioninclude:

-   (4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazol-4-yl)-quinolin-4-yl)amine;-   (4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazol-5-yl)-quinolin-4-yl)amine;-   (4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-2-yl)-quinolin-4-yl)amine;    and salts or solvates thereof, particularly pharmaceutically    acceptable salts or solvates thereof.

Other particularly preferred compounds of the present invention include:

-   (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine;    and salts or solvates thereof, particularly pharmaceutically    acceptable salts or solvates thereof.

Other most particularly preferred compounds of the present inventioninclude:

-   (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;-   (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine;    and salts or solvates thereof, particularly pharmaceutically    acceptable salts or solvates thereof.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereoisomers) and mixtures of these are included within the scope ofthe present invention. Likewise, it is understood that compounds offormula (I) may exist in tautomeric forms other than that shown in theformula and these are also included within the scope of the presentinvention.

Salts of the compounds of the present invention may comprise acidaddition salts derived from a nitrogen in the compound of formula (I).The therapeutic activity resides in the moiety derived from the compoundof the invention as defined herein and the identity of the othercomponent is of less importance although for therapeutic andprophylactic purposes it is, preferably, pharmaceutically acceptable tothe patient. Examples of pharmaceutically acceptable acid addition saltsinclude those derived from mineral acids, such as hydrochloric,hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, andorganic acids, such as tartaric, acetic, trifluoroacetic, citric, malic,lactic, fumaric, benzoic, glycolic, gluconic, succinic andmethanesulphonic and arylsulphonic, for example p-toluenesulphonic,acids.

According to a further aspect of the present invention there is provideda process for the preparation of a compound of formula (I) as definedabove which comprises the steps:

(a) the reaction of a compound of formula (II)

wherein X is as defined above;Y′ is CL′ and V′ is N;or Y′ is N and V′ is CL′;or Y′ is CL′ and V′ is CR²;or Y′ is CR² and V′ is CL′;wherein R² is as defined above, and L and L′ are suitable leavinggroups, with a compound of formula (III)UNH₂  (III)wherein U is as defined above, to prepare a compound of formula (IV)

and subsequently (b) reaction with appropriate reagent(s) to substitutethe group R¹ by replacement of the leaving group L′; and, if desired,(c) subsequently converting the compound of formula (I) thereby obtainedinto another compound of formula (I) by means of appropriate reagents.

Alternatively, the compound of formula (II) as defined above is reactedwith the appropriate reagents to substitute the group R¹ by replacementof the leaving group L′ and then the product thereby obtained (offormula (V) below) is reacted with the compound of formula (III) asdefined above, followed, if desired, by conversion of the compound offormula (I) thereby obtained into another compound of formula (I).

In a variant of this alternative the compound of formula (V)

wherein X, Y, V, U and L are as defined above, may be prepared by thereaction of a compound of formula (VI)

wherein V′ and Y′ are as defined above, with appropriate reagents tosubstitute the group R¹ for the leaving group L′ to prepare a compoundof formula (VII)

and subsequent reaction to incorporate the leaving group L. For example,a chloro leaving group can be incorporated by reaction of acorresponding 3,4-dihydropyrimidone with carbontetrachloride/triphenylphosphine in an appropriate solvent.

The group R¹ may, therefore, be substituted onto the basic ring systemby replacement of a suitable leaving group. This may, for example, becarried out by reaction of the corresponding aryl or heteroaryl stannanederivative with the corresponding compound of formula (IV) carrying theleaving group L′ in the appropriate position on the ring.

According to a further aspect of the present invention there is provideda process for the preparation of a compound of formula (I) as definedabove which comprises the steps:

(a) reacting a compound of formula (IV) as defined above withappropriate reagent(s) to prepare a compound of formula (VIII)

wherein X and U are as defined above;Y″ is CT and V″ is N;or Y″ is N and V″ is CT;or Y″ is CT and V″ is CR²;or Y″ is CR² and V″ is CT; wherein R² is as defined above and T is anappropriately functionalised group;and (b) subsequently converting the group T into the group R¹ by meansof appropriate reagent(s); and, if desired, (c) subsequently convertingthe compound of formula (I) thereby obtained into another compound offormula (I) by means of appropriate reagents.

In one alternative, the group T would represent a group Ar as definedabove carrying a formyl group (CHO).

Where T represents a group Ar carrying a formyl group the compound (offormula (VIIIa)) may be suitably prepared from the correspondingdioxolanyl substituted compound (of formula (VIIIb)), for example byacid hydrolysis. The dioxolanyl substituted compound may be prepared byreaction of a compound of formula (IV) with an appropriate reagent tosubstitute the relevant leaving group with the substituent carrying thedioxolanyl ring. This reagent could, for example, be an appropriateheteroaryl stannane derivative.

Therefore a suitable process may comprise reaction of a compound offormula (VIIIa) in which T is a group Ar carrying a formyl substituent(i.e. a —CHO group) with a compound of formula CH₃SO₂CH₂CH₂NH₂. Thereaction preferably involves a reductive amination by means of anappropriate reducing agent, for example sodium triacetoxyborohydride.

Alternatively, another suitable process may comprise oxidation of acompound of formula (VIIIc) in which T is a group Ar carrying asubstituent of formula CH₃SCH₂CH₂NHCH₂ or CH₃SOCH₂CH₂NHCH₂. Suitablemethods for the oxidation to the desired compound of formula (I) will bewell known to the person skilled in the art but include, for example,reaction with an organic peroxide, such as peracetic acid ormetachlorobenzoic acid, or reaction with an inorganic oxidising agent,such as OXONE®. The compound of formula (VIIIc) in which T is a group Arcarrying a substituent of formula CH₃SCH₂CH₂NHCH₂ or CH₃SOCH₂CH₂NHCH₂may be prepared by an analogous reaction to that described above, namelyreaction of a compound of formula (VIIIa) in which T is a group Arcarrying a formyl substituent (i.e. a —CHO group) with a compound offormula CH₃SCH₂CH₂NH₂ or CH₃SOCH₂CH₂NH₂ respectively.

Alternatively, an analogous scheme to those described above could beused wherein the substitution of the group R¹ onto the basic ring systemoccurs prior to the coupling reaction with the compound of formula(III).

According to a further alternative process the group T is converted intothe group R¹ by a de novo synthesis of a substituted heterocyclic systemusing appropriate agents. Such a process would involve standardsynthetic methodology known to the person skilled in the art forbuilding up the heterocylic ring system.

For example, T could represent a haloketone group as shown in thecompound of formula (IX) in scheme 1 below which, when coupled with anappropriate N-protected thioamide [compound of formula (XI) in scheme2], would result in the formation of an N-protected amino-substitutedthiazole system of formula (X).

Scheme 1 outlines, for example, the synthesis of derivatives carrying asubstituted thiazole ring as an R¹ substituent:

wherein halo is as previously defined (preferably iodo), and P′ in thecompound of formula (XI) is a suitable protecting group, such astrifluorocarbonyl.

An analogous process may be used to prepare compounds of formula (I)which carry R¹ in the 7-position of the basic ring system from astarting compound of formula (IVb)

via intermediates of formulae (Xb) and (XIb) which are respectivelyanalogous to those of formulae (Xa) and (XIb).

An appropriately substituted thioamide coupling reagent, suitable forpreparation of a thiazole ring system, may be prepared according toScheme 2:

Wherein in scheme 2 the trifluorocarbonyl protecting group in thecompounds of formula (XIV), (XV) and (XVIa) is equivalent to the groupP′ in scheme 1. Alternatively, an analogous scheme to those describedabove could be used wherein the substitution of the group R¹ onto thebasic ring system occurs prior to the coupling reaction with thecompound of formula (III).

Other substituted thioamides are prepared using analogous processes tothat shown above.

In general, the group R² will be present as a substituent in the basicring system prior to the introduction of the group R¹ or the group NHU.Where R² is other than hydrogen it may in certain circumstances benecessary to protect the group prior to performing the reaction steps tointroduce the R¹ and NHU substituents. Particular mention should be madeof the situation where R² is hydroxy; suitable protecting groups toensure non-interference with the subsequent reaction steps include the2-methoxyethoxymethyl ether (MEM) group or a bulky silyl protectinggroup such as tert-butyldiphenylsilyl (TBDPS).

Suitable protecting groups, methods for their introduction and methodsfor their removal would be well known to the person skilled in the art.For a description of protecting groups and their use see T. W. Greeneand P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 2nd edn.,John Wiley & Sons, New York, 1991.

Suitable leaving groups for L and L′ will be well known to those skilledin the art and include, for example, halo such as fluoro, chloro, bromoand iodo; sulphonyloxy groups such as methanesulphonyloxy andtoluene-p-sulphonyloxy; alkoxy groups; and triflate.

The coupling reaction referred to above with the compound of formula(III) is conveniently carried out in the presence of a suitable inertsolvent, for example a C₁₋₄ alkanol, such as isopropanol, a halogenatedhydrocarbon, an ether, an aromatic hydrocarbon or a dipolar aproticsolvent such as acetone, acetonitrile or DMSO at a non-extremetemperature, for example from 0 to 150° C., suitably 10 to 120° C.,preferably 50 to 100° C.

Optionally, the reaction is carried out in the presence of a base.Examples of suitable bases include an organic amine such astriethylamine, or an alkaline earth metal carbonate, hydride orhydroxide, such as sodium or potassium carbonate, hydride or hydroxide.

The compound of formula (I) may be obtained from this process in theform of a salt with the acid HL, wherein L is as hereinbefore defined,or as the free base by treating the salt with a base as hereinbeforedefined.

The compounds of formulae (II) and (III) as defined above, the reagentsto substitute the group R¹, and the reagent(s) to convert the group Tinto the group R¹ are either readily available or can be readilysynthesised by those skilled in the art using conventional methods oforganic synthesis.

As indicated above, the compound of formula (I) prepared may beconverted to another compound of formula (I) by chemical transformationof the appropriate substituent or substituents using appropriatechemical methods (see for example, J. March “Advanced OrganicChemistry”, Edition III, Wiley Interscience, 1985).

For example, a compound containing an alkylthio group may be oxidised tothe corresponding sulphinyl or sulphonyl compound by use of an organicperoxide (e.g. benzoyl peroxide) or suitable inorganic oxidant (egOXONE®).

A compound containing a nitro substituent may be reduced to thecorresponding amino-compound, e.g. by use of hydrogen and an appropriatecatalyst (if there are no other susceptible groups), by use of RaneyNickel and hydrazine hydrate or by use of iron/acetic acid.

Amino substituents may be acylated by use of an acid chloride or ananhydride under appropriate conditions. Equally an amide group may becleaved to the amino compound by treatment with, for example, diluteaqueous base.

An amino substituent may also be converted to a dimethylaminosubstituent by reaction with formic acid and sodium cyanoborohydride.Similarly, reaction of a primary or secondary amino group with anothersuitable aldehyde under reducing conditions will lead to thecorresponding substituted amine.

All of the above-mentioned chemical transformations may also be used toconvert any relevant intermediate compound to another intermediatecompound prior to the final reaction to prepare a compound of formula(I); this would thus include their use to convert one compound offormula (III) to a further compound of formula (III) prior to anysubsequent reaction.

Various intermediate compounds used in the above-mentioned processes,including but not limited to certain of the compounds of formulae (II),(III), (IV), (V), (VI), (VII) and (VIII) as illustrated above, are noveland thus represent a further aspect of the present invention.

In particular, a further aspect of the present invention is intermediatecompounds of formulae (VIIIa) and (VIIIb) defined above, with theexception of the following compounds:

-   (1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;-   5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;-   (4-Benzyloxy-phenyl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-quinazolin-4-yl)-amine;-   5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde;-   (1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-quinazolin-4-yl)-amine;-   5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-furan-2-carbaldehyde;-   5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-1-methyl-pyrrole-2-carbaldehyde;-   (1-Benzyl-1H-indazol-5-yl)-(7-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-quinazolin-4-yl)-amine;-   5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl)-furan-2-carbaldehyde.

In particular, a yet further aspect of the present invention isintermediate compounds of formula (VIIIc) as defined above;

with the proviso that the following compound is excluded:

-   (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphinyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine.

In particular, another further aspect of the present invention isintermediate compounds of formulae (X), (XI), (XII), (XIII), (XIV), (XV)and (XVI) as defined above.

The compounds of formula (I) and salts thereof have anticancer activityas demonstrated hereinafter by their inhibition of the protein tyrosinekinase c-erbB-2, c-erbB-4 and/or EGF-R enzymes and their effect onselected cell lines whose growth is dependent on c-erbB-2 or EGF-rtyrosine kinase activity. Certain compounds of formula (I) are alsodemonstrated hereinafter to inhibit Ick and/or zap70 protein tyrosinekinase enzymes and are expected to have activity in disease conditionsin which T cells are hyperactive.

The present invention thus also provides compounds of formula (I) andpharmaceutically acceptable salts or solvates thereof for use in medicaltherapy, and particularly in the treatment of disorders mediated byaberrant protein tyrosine kinase activity such as human malignancies andthe other disorders mentioned above. The compounds of the presentinvention are especially useful for the treatment of disorders caused byaberrant c-erbB-2 and/or EGF-r and/or Ick activity such as breast,ovarian, gastric, pancreatic, non-small cell lung, bladder, head andneck cancers, psoriasis and rheumatoid arthritis.

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from a disorder mediated by aberrantprotein tyrosine kinase activity, including susceptible malignancies,which comprises administering to said subject an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, in therapy.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, in the preparation of a medicament for the treatment of cancerand malignant tumours.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, in the preparation of a medicament for the treatment ofpsoriasis.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, in the preparation of a medicament for the treatment ofrheumatoid arthritis.

Whilst it is possible for the compounds, salts or solvates of thepresent invention to be administered as the new chemical, it ispreferred to present them in the form of a pharmaceutical formulation.

According to a further feature of the present invention there isprovided a pharmaceutical formulation comprising at least one compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, together with one or more pharmaceutically acceptable carriers,diluents or excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain for example 0.5 mg to 1 g, preferably 70 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I)depending on the condition being treated, the route of administrationand the age, weight and condition of the patient.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists which may be generated by means ofvarious types of metered dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

Preferred unit dosage formulations are those containing a daily dose orsub-dose, as herein above recited, or an appropriate fraction thereof,of an active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

The animal requiring treatment with a compound, salt or solvate of thepresent invention is usually a mammal, such as a human being.

A therapeutically effective amount of a compound, salt or solvate of thepresent invention will depend upon a number of factors including, forexample, the age and weight of the animal, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration, and will ultimately be at the discretion ofthe attendant physician or veterinarian However, an effective amount ofa compound of the present invention for the treatment of neoplasticgrowth, for example colon or breast carcinoma, will generally be in therange of 0.1 to 100 mg/kg body weight of recipient (mammal) per day andmore usually in the range of 1 to 10 mg/kg body weight per day. Thus,for a 70 kg adult mammal, the actual amount per day would usually befrom 70 to 700 mg and this amount may be given in a single dose per dayor more usually in a number (such as two, three, four, five or six) ofsub-doses per day such that the total daily dose is the same. Aneffective amount of a salt or solvate of the present invention may bedetermined as a proportion of the effective amount of the compound perse. It is envisaged that similar dosages would be appropriate fortreatment of the other conditions referred to above.

The compounds of the present invention and their salts and solvates maybe employed alone or in combination with other therapeutic agents forthe treatment of the above-mentioned conditions. In particular, inanti-cancer therapy, combination with other chemotherapeutic, hormonalor antibody agents is envisaged. Combination therapies according to thepresent invention thus comprise the administration of at least onecompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof and at least one other pharmaceutically active agent. Thecompound(s) of formula (I) and the other pharmaceutically activeagent(s) may be administered together or separately and, whenadministered separately this may occur simultaneously or sequentially inany order. The amounts of the compound(s) of formula (I) and the otherpharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect.

Certain embodiments of the present invention will now be illustrated byway of example only. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds.

¹H NMR spectra were obtained at 500 MHz on a Bruker AMX500spectrophotometer, on a Bruker spectrophotometer at 300 MHz, on a BrukerAC250 or Bruker AM250 spectrophotometer at 250 MHz and on a Varian UnityPlus NMR spectrophotometer at 300 or 400 MHz. J values are given in Hz.Mass spectra were obtained on one of the following machines: VGMicromass Platform (electrospray positive or negative), HP5989A Engine(thermospray positive) or Finnigan-MAT LCQ (ion trap) mass spectrometer.Analytical thin layer chromatography (tlc) was used to verify the purityof some intermediates which could not be isolated or which were toounstable for full characterisation, and to follow the progress ofreactions. Unless otherwise stated, this was done using silica gel(Merck Silica Gel 60 F254). Unless otherwise stated, columnchromatography for the purification of some compounds used Merck Silicagel 60 (Art. 1.09385, 230-400 mesh), and the stated solvent system underpressure.

Petrol refers to petroleum ether, either the fraction boiling at 40-60°C., or at 60-80° C.

Ether refers to diethylether.

DMSO refers to dimethylsulphoxide.

THF refers to tetrahydrofuran.

HPLC refers to high pressure liquid chromatography.

NMM refers to N-methylmorpholine

Useful preparative techniques are described in WO96/09294, WO97/03069,WO97/13771, WO95/19774, WO96/40142 and WO97/30034; also described inthese publications are appropriate intermediate compounds other thanthose detailed below.

Preparation processes specified in the prior art or in the experimentaldetails below for compounds with a particular basic ring system (1) to(6) above may be suitably adapted for others of these basic ringsystems.

General Procedures

(A) Reaction of an Amine with a Bicyclic Species Containing a4-Chloropyrimidine or 4-Chloropyridine Ring

The optionally substituted bicyclic species and the specified amine weremixed in an appropriate solvent (typically acetonitrile unless otherwisespecified, although ethanol, 2-propanol or DMSO may also be used), andheated to reflux. When the reaction was complete (as judged by tlc), thereaction mixture was allowed to cool. The resulting suspension wasdiluted, e.g. with acetone, and the solid collected by filtration,washing e.g. with excess acetone, and dried at 60° C. in vacuo, givingthe product as the hydrochloride salt. If the free base was required(e.g. for further reaction), this was obtained by treatment with a basee.g. triethylamine; purification by chromatography was then performed ifrequired.

(B) Reaction of a Product from Procedure (A) with a Heteroaryl TinReagent

A stirred mixture of the product from Procedure (A), (containing asuitable leaving group such as chloro, bromo, iodo or triflate), aheteroaryl stannane and a suitable palladium catalyst, such asbis(triphenylphosphine)palladium (II) chloride or1,4-bis(diphenylphosphino)butane palladium (II) chloride (prepared asdescribed in C. E. Housecroft et. al., Inorg. Chem., (1991), 30(1),125-130), together with other appropriate additives (such asdiisopropylethylamine or lithium chloride), were heated at reflux in drydioxane or another suitable solvent (e.g. DMF) under nitrogen until thereaction was complete. The resulting mixture was generally purified bychromatography on silica.

(C) Removal of a 1,3-Dioxolan-2-yl Protecting Group to Liberate analdehyde

The compound containing the 1,3-dioxolan-2-yl group was suspended in anappropriate solvent, e.g. THF and treated with hydrochloric acid, eitheras an aqueous solution (e.g. 2N) or as a solution in dioxane (e.g. 4molar) and stirred at ambient temperature until the reaction was judgedcomplete (e.g. by tlc or LCMS analysis). Generally the mixture wasdiluted with water, and the resulting precipitate was collected byfiltration, washed with water and dried to give the aldehyde.

(D) Reaction of an Aldehyde with an Amine by Reductive Amination

An aldehyde (such as the product of General Procedure C) and therequired primary or secondary amine were stirred together in a suitablesolvent (such as dichloromethane) containing glacial acetic acid (4Amolecular sieves may also be present) for ca. 1 h. A suitable reducingagent, such as sodium (triacetoxy) borohydride was then added andstirring continued under nitrogen until the reaction was complete (asjudged by hplc or tlc). The resulting mixture was washed with an aqueousbasic solution (e.g. sodium or potassium carbonate) and extracted with asuitable solvent, e.g. dichloromethane. The dried organic phase wasevaporated and the residue purified either by column chromatography orby Bond Elut™ cartridge. If desired, the isolated material was thenconverted into the hydrochloride salt e.g. by treatment with etherealhydrogen chloride.

(E) Reaction Sequence to Prepare Appropriately Substituted Thioamides

E-1 Reaction of an Aminosulfide with Chloroacetonitrile

To a stirred mixture of an aminosulfide and a suitable base such assodium bicarbonate or sodium carbonate in an appropriate solvent(typically acetonitrile, although DMF or dioxane can be used) was addedchloroacetonitrile dropwise. The resulting mixture was heated to refluxuntil the reaction was complete. The solid was filtered and the filtratewas concentrated to provide the corresponding aminonitrile.

E-2 Trifluoroacetamide Protection of an Aminonitrile

A solution of the aminonitrile (such as the product of general procedureA) and an amine base, such as triethylamine or NMM in a suitable solvent(e.g. dichloromethane), was cooled to 0° C. and trifluoroaceticanhydride was added dropwise. The resulting mixture was stirred at roomtemperature until the reaction was complete. Water was added and themixture was extracted with a suitable solvent (e.g. dichloromethane),the organic layer was dried over anhydrous magnesium sulfate andconcentrated. The crude product was purified by column chromatography toprovide the corresponding trifluoroacetamide.

E-3 Oxidation of a Cyanosulfide

To a stirred solution of a sulfide (such as the product of generalprocedure E1) in a suitable solvent (typically methano/water (2:1),although dichloromethane can be used) cooled to 0° C. was added anoxidizing agent (typically oxone, although MCPBA can be used). Theresulting mixture was stirred at room temperature until the reaction wascomplete. The reaction was concentrated to remove any organic solvents,diluted with water, and extracted with an appropriate solvent (e.g.dichloromethane). The organic layer was dried and concentrated toprovide the corresponding cyanosulfone.

E-4 Preparation of Thioamides

To a solution of a cyanosulfone (such as the product of generalprocedure E-3) and an organic base (e.g. triethylamine) in THF was addedhydrogen sulfide gas. The resulting mixture was stirred at roomtemperature until the reaction was complete. The mixture wasconcentrated and triturated with hexane to provide thioamide.

(F) Reaction Sequence to Prepare an Optionally Substituted Thiazole

F-1 Reaction of a Vinylstannane with a Product from Procedure (A)

A stirred mixture of the optionally substituted bicyclic4-anilinopyrimidine species, tributyl(1-ethoxyvinyl)stannane (1 to 5molar equivalents), and a suitable palladium catalyst (0.03 to 0.1 molarequivalents), such as bis(triphenylphosphine) palladium (II) chloride ortetrakis(triphenylphosphine) palladium (0) was heated at reflux in anappropriate solvent (typically acetonitrile, although DMF or dioxane canbe used) until the reaction was complete. The resulting mixture wasconcentrated and generally purified by trituration with diethyl ether toprovide the corresponding bicyclic pyrimidine vinyl ether.

F-2 Reaction of a Product from Procedure (F-1) with a BrominationReagent

A bicyclic pyrimidine vinyl ether (such as the product of generalprocedure F-1) and 1 equivalent of a bromination reagent, such asN-bromosuccinimide or bromine, were stirred at 0° C. in a suitablesolvent (typically 10% aqueous THF or dichloromethane) until thereaction was complete. The resulting mixture was dried over anhydrousmagnesium sulfate and concentrated, or in the case of bromine the solidwas filtered, to provide the corresponding α-bromoketone.

F-3 Reaction of a Product from Procedure (F-2) with a Product fromProcedure (E-4)

A stirred mixture of an α-bromoketone (such as the product of generalprocedure F-2) and thioamide from Procedure E-4 in a 1:1 molar ratio washeated to 70-100° C. in an appropriate solvent (typically DMF, althoughacetonitrile and THF can be used) until the reaction was complete. Theresulting mixture was washed with an aqueous basic solution (e.g. sodiumcarbonate) and extracted with a suitable solvent, e.g. ethyl acetate.The dried organic layer was concentrated and the residue was purified bycolumn chromatography to provide the corresponding trifluoroacetamideaminothiazole.

F-4 Removal of a Trifluoroacetamide Protecting Group to Liberate anAminothiazole

A mixture of a trifluoroacetamide protected aminothiazole (such as theproduct of general procedure F-3) in 2M NaOH/methanol (1:1) was stirredat room temperature until the reaction was complete. The mixture wasconcentrated, poured into water and extracted with an appropriatesolvent e.g. 10% MeOH/dichloromethane. The dried organic layer wasconcentrated, then dissolved in ethyl acetate/MeOH (1:1) and treatedwith 4M HCl/dioxane. The resulting solid was filtered to provide thecorresponding amine hydrochloride salt.

Synthesis of IntermediatesN-5[N-tert-Butoxycarbonyl)amino]-2-chloropyridine

A stirred solution of 6-chloronicotinic acid (47.3 g),diphenylphosphoryl azide (89.6 g) and triethylamine (46 ml) in t-butanol(240 ml) were heated under reflux under nitrogen for 2.5 hours. Thesolution was cooled and concentrated in vacuo. The syrupy residue waspoured into 3 liters of a rapidly stirred solution of 0.33N aqueoussodium carbonate. The precipitate was stirred for one hour and filtered.The solid was washed with water and dried in vacuo at 70° C. to give thetitle compound (62 g) as a pale brown solid; m.p. 144-146° C.; δH[²H₆]-DMSO 8.25 (1H, d), 7.95 (1H, bd), 7.25 (1H, d), 6.65 (1H, bs),1.51 (9H, s); m/z (M+1)⁺ 229.

This material may subsequently be carried forward to the appropriatelysubstituted pyridopyrimidine intermediate according to the procedures asdescribed in WO95/19774, J. Med. Chem., 1996, 39, pp 1823-1835, and J.Chem. Soc., Perkin Trans. 1, 1996, pp 2221-2226. Specific compounds madeby such procedures include 6-chloro-pyrido[3,4-d]pyrimidin-4-one and4,6-dichloro-pyrido[3,4-d]pyrimidine.

2-Amino-4-fluoro-5-iodo-benzoic acid

To a vigorously stirred solution of dichloromethane (700 ml), methanol(320 ml), and 2-amino-4-fluoro-benzoic acid (33.35 grams, 215 mmoles)was added solid sodium hydrogencarbonate (110 grams, 1.31 moles)followed by portion addition of benzyltrimethyl ammonium dichloroiodate(82.5 grams, 237 mmoles). The mixture was allowed to stir for 48 hours.The mixture was filtered to remove the insolubles. The remaining solidresidue was washed with 200 ml of dichloromethane. The filtrate wasconcentrated and redissolved in a one to one mixture of ethyl acetate (1liter) and a 0.2 N solution of sodium hydroxide (1 liter), added to a 2liter separatory funnel and extracted. The organic layer was washed withan additional 200 ml of water. The aqueous layers were combined andacidified with 2N hydrochloric acid. The resulting precipitate wascollected by suction filtration, washed with water and dried undervacuum at 60° C. to yield 46.5 grams (77%) of the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ: 8.04 (d, 1H), 7.1 (s, broad, 2H), 6.63 (d, 1H).ESI-MS m/z 280 (M−1).

4-Fluoro-5-iodo-isatoic anhydride

Anhydrous dioxane (0.5 liters), 2-amino-4-fluoro-5-iodo-benzoic acid (46grams, 164 mmoles), and trichloromethylchloroformate (97.4 grams, 492mmoles) were added to a one liter one neck flask equipped with amagnetic stir bar and reflux condenser. The solution was placed underanhydrous nitrogen, stirred and heated to reflux for 16 hours. Thereaction mixture was allowed to cool and was poured into one liter ofhexanes. The solid was collected by suction filtration, washed with anadditional 0.5 liters of hexanes, and dried under vacuum at roomtemperature to yield 45.5 grams (90%) of the title compound. ¹H NMR (400MHz, DMSO-d₆) δ: 11.86 (s, 1H), 8.24 (d, 1H), 6.84 (d, 1H). ESI-MS m/z308 (M+1).

4-Chloro-6-bromoquinazoline and 4-Chloro-6-iodoquinazoline were preparedas described in WO 96/09294.

4-Hydroxy-6-iodo-7-fluoroquinazoline

Dimethylformamide (0.5 liters), 4-fluoro-5-iodo-isatoic anhydride (45grams, 147 mmoles), and formamidine acetate (45.92 grams, 441 mmoles),were combined in a one liter one-neck flask fitted with a magnetic stirbar. The mixture was placed under anhydrous nitrogen and heated at 110°C. for 6 hours. The mixture was allowed to cool, followed byconcentrating the reaction mixture to one third its original volume onthe rotary evaporator. The resulting mixture was poured onto 3 liters ofice water. The resulting precipitated solid was collected by suctionfiltration. The solid was washed with an additional one liter ofdistilled water. The resulting solid was dried under vacuum at 70° C. toyield 38.9 grams (91%) of the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ: 12.43 (s, 1H), 8.46 (d, 1H), 8.12 (s, 1H), 7.49 (d, 1H). ESI-MS m/z291 (M+1).

4-Chloro-6-iodo-7-fluoro-quinazoline hydrochloride

Thionyl chloride (0.6 liters), 4-hydroxy-6-iodo-7-fluoro-quinazoline (36grams, 124 mmoles), and dimethylformamide (6 ml) were combined in a oneliter one-neck flask fitted with a magnetic stir bar. The mixture wasplaced under anhydrous nitrogen and heated to a gentle reflux for 24hours. The mixture was allowed to cool, followed by concentrating thereaction mixture to a thick yellowish residue. To this residue was addeddichloromethane (0.1 liter) and toluene (0.1 liter). The mixture wasconcentrated to dryness. This procedure was repeated two additionaltimes. To the resulting solid was added 0.5 liters of drydichloromethane and the mixture was stirred for one hour. The mixturewas filtered and the remaining solids were washed with minimaldichloromethane. The dichoromethane filtrates were combined,concentrated to a solid, and dried under vacuum at room temperature toyield 28.6 grams (67%) of the title compound. ¹H NMR (400 MHz, CDCl₃-d₁)δ: 9.03 (s, 1H), 8.76 (d, 1H), 7.69 (d, 1H). ESI-MS m/z 309 (M+1).

2-Bromo-4-(1,3-dioxolan-2-yl) thiazole

2-Bromothiazole-4-carbaldehyde (6.56 g, 34.17 mmol) [A. T. Ung, S. G.Pyne/Tetrahedron: Asymmetry 9 (1998) 1395-1407] and ethylene glycol(5.72 ml, 102.5 mmol) were heated under reflux in toluene (50 ml), witha Dean and Stark trap fitted, for 18 hr. The product was concentratedand purified by column chromatography (15% ethyl acetate hexane) to givethe product as a yellow solid (6.03 g); m/z 236, 238.

4-(1,3-Dioxolan-2-yl)-5-(tributylstannyl)thiazole

2-Bromo-4-(1,3-dioxolan-2-yl) thiazole (6.4 g, 27.14 mmol) was stirredat 78° C. in dry THF (38 ml). 1.6M n butyl lithium in hexane (18.6 ml,29.78 mmol) was added dropwise under nitrogen. After 30 min at thistemperature, tributyl tin chloride (7.35 ml, 27.14 mmol) was addeddropwise. The reaction was allowed to warm to 0° and water (20 ml) wasadded. The product was extracted into ether (3×100 ml). The combinedorganic extracts were dried (MgSO₄) and evaporated. The residue wastriturated with isohexane (3×100 ml) and the mother liquors weredecanted, combined and concentrated to give a brown oil (11.88 g); m/z444-450.

1-N-Benzyl-5-nitro-1H-indazole and 2-N-Benzyl-5-nitro-1H-indazole

A stirred mixture of 5-nitroindazole (50 g), potassium carbonate (46.6g, 1.1 equiv.) and benzyl bromide (57.6 g, 1.1 equiv) inN,N-dimethylformamide (500 ml) was heated at 75° C. for a period of 4hours. The reaction was then cooled and water (500 ml) was graduallyadded to precipitate the product which was filtered off and washed withwater (50 ml) and dried in the air at ambient temperature. The weight ofpale yellow solid thus obtained was 72.3 g (93%), m.p. 95-97° C.; HPLC(Partisil 5, dichloromethane, 4 ml/min, 250 nm) gave an isomer ratio(1-N-benzyl:2-N-benzyl) of 63:37 (RT-1N 3.4 min, RT-2N 6.6 min). To afiltered solution of the mixed regioisomers (100 g) in acetone (470 ml)at room temperature was added, gradually with stirring, water (156 ml)and the mixture was stirred for one hour. The resultant yellowcrystalline solid was filtered off and dried in the air at ambienttemperature to give 36.4 g (34%) of material; m.p. 124-126° C.; HPLCshowed an isomer ratio (1-N-benzyl:2-N-benzyl) of 96:4; (CDCl₃) 5.58(2H, s, CH₂), 7.12-7.15 (2H) & 7.22-7.29 (3H)-(phenyl), 7.33 (1H, dt,J=1 Hz & 9 Hz, H-7), 8.15 (1H, dd, J=2 Hz & 9 Hz, H-6), 8.19 (1H, d, J=1Hz, H-3), 8.67 (1H, dd, J=1 Hz & 2 Hz, H-4).

Also note the published method in FR 5600, 8 Jan. 1968.

5-Amino-1-N-benzyl-1H-indazole

1-Benzyl-5-nitroindazole (400 g) was suspended in ethanol (5 liter) andhydrogenated in the presence of 5% platinum on carbon catalyst (20 g)operating at 1 bar pressure and 50-60° C. When hydrogen uptake wascomplete the reactor contents were heated to 70° C., discharged andfiltered while still hot and the filtrate concentrated to ˜4 liter whichcaused some crystallisation. Water (4 liter) was then gradually addedwith stirring and the mixture was stirred at 5° C. overnight. Theresultant crystals were filtered off and air-dried at ambienttemperature to give 305 g (86%) of material, m.p. 150-152° C.; HPLC(Supelcosil ABZ+, gradient 0.05% trifluoroacetic acid in water/0.05%trifluoroacetic acid in acetonitrile, 1.5 ml/min, 220 nm) showed <1% ofthe corresponding 2-N-isomer (RT-1N 6.03 min, RT-2N 5.29 min); (CDCl₃)3.3-3.8 (2H, broad s, NH₂), 5.47 (2H, s, CH₂), 6.74 (1H, dd, J=2 Hz & 9Hz, H-6), 6.87 (1H, dd, J=1 Hz & 2 Hz, H-4), 7.06-7.11 (3H) & 7.17-7.25(3H)-(phenyl & H-7), 7.77 (1H, d, J=1 Hz, H-3).

Also note the published method in FR 5600, 8 Jan. 1968.

1-Benzyl-3-methyl-5-nitro-1H-indazole

2-Fluoro-5-nitroacetophenone (H. Sato et al, Bioorganic and MedicinalChemistry Letters, 5(3), 233-236, 1995) (0.24 g) was treated withtriethylamine (0.73 ml) and benzyl hydrazine dihydrochloride (0.255 g)in ethanol (20 ml) at reflux under N₂ for 8 days. The mixture was cooledand the solid 1-benzyl-3-methyl-5-nitroindazole (0.16 g) was collectedby filtration; m/z (M+1)⁺ 268.

1-Benzyl-3-methyl-1H-indazol-5-ylamine

1-Benzyl-3-methyl-5-nitroindazole (0.15 g) in THF (15 ml) was treatedwith platinum on carbon (0.05 g, 5%) under an atmosphere of hydrogen atroom temperature. When hydrogen uptake was complete, the mixture wasfiltered and concentrated in vacuo to give the title compound; m/z(M+1)⁺ 268.

Further Amino-Indazole Intermediates

The relevant nitro-substituted 1H-indazole was treated with a base suchas potassium carbonate or sodium hydroxide in a suitable solvent, suchas acetone or acetonitrile. The appropriate aryl halide or heteroarylhalide was added and the reaction mixture heated or stirred at roomtemperature overnight.

Subsequent concentration in vacuo and chromatography on silica gave thedesired 1-substituted nitro-1H-indazoles. Hydrogenation was carried outby analogy with the preparation of 5-amino-1-benzyl-1H-indole describedabove.

Amines prepared by such methods include:—

-   5-Amino-1-benzyl-1H-indazole; m/z (M+1)⁺ 224-   5-Amino-1-(2-fluorobenzyl)-1H-indazole; m/z (M+1)⁺ 242-   5-Amino-1-(3-fluorobenzyl)-1H-indazole; m/z (M+1)⁺ 242-   5-Amino-1-(4-fluorobenzyl)-1H-indazole; m/z (M+1)⁺ 242-   5-Amino-1-(2-pyridylmethyl)-1H-indazole; m/z (M+1)⁺ 225-   5-Amino-1-(3-pyridylmethyl)-1H-indazole; m/z (M+1)⁺ 225-   5-Amino-1-(4-pyridylmethyl)-1H-indazole; m/z (M+1)⁺ 225-   5-Amino-1-(2,3-difluorobenzyl)-1H-indazole; m/z (M+1)⁺ 260-   5-Amino-1-(3,5-difluorobenzyl)-1H-indazole; m/z (M+1)⁺ 260.

1-Benzenesulphonylindol-5-yl-amine was prepared according to thepublished method (J. Org. Chem., 55, 1379-90, (1990)).

4-Benzyloxyaniline is commercially available as the hydrochloride salt;this is treated with aqueous sodium carbonate solution, and the mixtureextracted with ethyl acetate; the organic solution is dried (MgSO₄) andconcentrated to give the free base as a brown solid, used withoutfurther purification.

Other substituted anilines were in general prepared by analogous methodsto those outlined in WO 96/09294 and/or as follows:

Step 1: Preparation of the Precursor Nitro-Compounds

4-Nitrophenol (or an appropriate substituted analogue, such as3-chloro-4-nitrophenol) was treated with a base such as potassiumcarbonate or sodium hydroxide in an appropriate solvent, such as acetoneor acetonitrile. The appropriate aryl or heteroaryl halide was added andthe reaction mixture heated or stirred at room temperature overnight.

Purification A: Most of the acetonitrile was removed in vacuo, and theresidue was partitioned between water and dichloromethane. The aqueouslayer was extracted with further dichloromethane (×2), and the combineddichloromethane layers were concentrated in vacuo.

Purification B: removal of insoluble material by filtration, followed byconcentration of the reaction mixture in vacuo, and chromatography onsilica.

Step 2: Reduction to the Corresponding Aniline

The precursor nitro compound was reduced by catalytic hydrogenation atatmospheric pressure using 5% Pt/carbon, in a suitable solvent (egethanol, THF, or mixtures thereof to promote solubility). When reductionwas complete, the mixture was filtered through Harborlite™, washing withexcess solvent, and the resulting solution concentrated in vacuo to givethe desired aniline. In some cases, the anilines were acidified with HCl(e.g. in a solution in dioxane) to give the corresponding hydrochloridesalt.

Anilines prepared by such methods include:

-   4-(2-Fluorobenzyloxy)aniline; m/z (M+1)⁺ 218-   4-(3-Fluorobenzyloxy)aniline; m/z (M+1)⁺ 218-   4-(4-Fluorobenzyloxy)aniline; m/z (M+1)⁺ 218-   3-Chloro-4-(2-fluorobenzyloxy)aniline; m/z (M+1)⁺ 252-   3-Chloro-4-(3-fluorobenzyloxy)aniline; m/z (M+1)⁺ 252-   3-Chloro-4-(4-fluorobenzyloxy)aniline; m/z (M+1)⁺ 252-   4-Benzyloxy-3-chloroaniline; m/z (M+1)⁺ 234    and, in appropriate cases, their hydrochloride salts.

4-Benzenesulphonylaniline was prepared by the published method (Helv.Chim. Acta., 1983, 66(4), p 1046.

4-Benzyloxy-3-trifluoromethyl-nitrobenzene

60% NaH dispersion (1.4 g, 33.5 mmol) in mineral oil was washed withhexanes and then suspended in DMF (10 ml). To this NaH suspension inDMF, added benzyl alcohol (2.8 ml, 26.3 mmol) with water bath to keepthe temperature below 30° C. The reaction mixture was stirred until theevolution of the hydrogen gas ceased. To a solution of2-fluoro-5-nitrobenzotrifluoride (5.0 g, 23.9 mmol) in DMF (20 ml) wasadded the benzyl alkoxide solution slowly at 0° C. Upon the completionof the addition, the ice bath was removed and the reaction mixture wasstirred at room temperature for 2 hours. The reaction mixture was pouredinto 200 ml ice water, stirred until the yellow solid was formed.Filtered and the solid was washed with water and then trituated withpentane. 5.9 g yellow solid was collected (yield: 83%). ESI-MS m/z 298(M+H)⁺

4-Benzyloxy-3-trifluoromethyl-aniline

Raney Ni suspension (about 200 mg Ni) was stirred with methanol. Thesupernate was decanted. This was repeated twice and then fresh methanolwas added. To this suspension of Ni in methanol, was added2-O-benzyl-5-nitrotrifluoride (375 mg, 1.26 mmol). With the water bathto keep the temperature below 30° C., the hydrazine hydrate (189 mg,3.79 mmol) was slowly added. Upon the completion of addition, thereaction mixture was stirred at room temperature for 10 minutes and then45° C. until evolution of nitrogen gas ceased. Filtered through Celite®and the filtrate was concentrated under reduced pressure. 336 mg thickyellow syrup was obtained (yield: 100%). ESI-MS m/z 268 (M+H)⁺.

4-(Tributylstannyl)thiazole-2-carbaldehyde

4-Bromo-2-(tributylstannyl)thiazole (T. R. Kelly and F. Lang,Tetrahedron Lett., 36, 9293, (1995)) (15.0 g) was dissolved in THF (150ml) under a nitrogen atmosphere, cooled to −85 C and treated with t-BuLi(1.7M, in pentane, 43 ml). The mixture was stirred at −85 C for 30 min,and then N-formylmorpholine (8.4 g) was added by syringe. After furtherstirring at −85 C for 10 min the mixture was allowed to warm to roomtemperature. Water (200 ml) was added and the mixture was extracted withdiethyl ether (4×100 ml). The combined ethereal extracts were washedwith water, dried (NaSO₄), and concentrated in vacuo. Chromatography onsilica, eluting with 10% ether/i-hexane, gave the title compound as ayellow oil; [²H₆]DMSO 10.03 (1H, s), 8.29 (1H, s), 1.55 (6H, q),1.21-1.37 (6H, m), 1.09-1.20 (6H, m), 0.85 (9H, t).

(1-Benzyl-1H-indazol-5-yl)-(6-chloropyrido[3,4-d]pyrimidin-4-yl)-aminehydrochloride

Prepared according to Procedure A from 1-benzyl-1H-indazol-5-ylamine and4,6-dichloropyrido[3,4-d]pyrimidine; δH [²H₆]-DMSO 9.08 (1H, s), 8.92(1H, s), 8.82 (1H, s), 8.23 (1H, d), 8.19 (1H, s), 7.80 (1H, d), 7.70(1H, dd), 7.38-7.22 (5H, m), 5.69 (2H, s); m/z (M+1)⁺ 387.

(1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-pyrido[3,4-d]-pyrimidin-4-yl)-amine

(1-Benzyl-1H-indazol-5-yl)-(6-chloropyrido[3,4-d]pyrimidin-4-yl)-amine(4.28 g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (J. Chem Soc.,Chem. Commun., (1988), p 560) (10 g) and1,4-bis(diphenylphosphino)butane palladium (II) chloride (1 g) wereheated at reflux in dioxane (150 ml) for 24 hr (Procedure B). Thesolvent was removed in vacuo and the residue chromatographed on silica.Subsequent trituration gave the title compound as a yellow solid;[²H₆]-DMSO 10.46 (1H, s), 9.17 (1H, s), 8.74 (1H, s), 8.52 (1H, s), 8.23(1H, s), 8.18 (1H, s), 7.80-7.68 (2H, m), 7.41-7.22 (5H, m), 7.17 (1H,d), 6.80 (1H, d), 6.06 (1H, s), 5.71 (2H, s), 4.20-3.96 (4H, m).

5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde

(1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolanyl]-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(3.03 g) and 2N HCl (50 ml) were stirred in THF (50 ml) for 16 hr. Theresulting precipitate was filtered and washed with water to give thehydrochloride salt of the product; δH [²H₆]DMSO 11.70 (1H, s), 9.74 (1H,s) 9.30 (1H, s), 9.27 (1H, s), 8.85 (1H, s), 8.23 (1H, s), 8.18 (1H, s),7.68-7.87 (3H, m), 7.55 (1H, d), 7.22-7.38 (5H, m), 5.71 (2H, s).Subsequent neutralisation with triethylamine in ethano/water gave thetitle compound; δH [²H₆]-DMSO 9.64 (1H, s), 9.19 (1H, s), 9.09 (1H, s),8.72 (1H, s), 8.12 (2H, m), 7.71 (2H, m), 7.63 (1H, dd), 7.43 (1H, d),7.20 (5H, m), 5.62 (2H, s).

(4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine

Prepared according to Procedure A from 4-benzyloxyaniline and4,6-dichloro-pyrido[3,4-d]pyrimidine; (CDCl₃) 9.11 (1H, s), 8.78 (1H,s), 7.75 (1H, d), 7.56 (2H, dd), 7.40 (5H, m), 7.15 (2H, d), 5.10 (2H,s); m/z (M+1)⁺ 409.

5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde

(4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (4.0 g,11.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (J. Chem.Soc., Chem. Commun., (1988), 560) (6.0 g, 14.0 mmol) were reactedtogether in a procedure analogous to Procedure B above for 20 hrs. Thereaction mixture was allowed to cool, 1N HCl (50 ml) added and stirredat room temperature for 15 minutes. The reaction was filtered and theresidue washed with dioxane (20 ml) and 2N HCl (20 ml). The combinedfiltrate and washings were stirred at room temperature for a furtherhour. The dioxane was removed under vacuum, the reaction diluted withwater and the solid which precipitated was collected by filtration, andwashed with water, iso-hexane and acetone. This precipitate wasconverted to the free base by partitioning into a mixture oftriethylamine, ethyl acetate and water. The organic phase was washedwith water, dried (magnesium sulphate) and the solvent removed undervacuum. The residue was triturated with iso-hexane/ethyl acetate to givethe product (2.41 g, 52%) as a yellow solid;

[²H₆]-DMSO 10.60 (1H, b, NH), 9.83 (1H, s, CHO), 9.30 (1H, s, 2-H), 9.08(1H, s, 5-H or 8-H), 8.76 (1H, s, 5-H or 8-H), 7.89 (1H, d, furan-H),7.82 (2H, d, 2′-H, 6′-H), 7.65-7.42 (6H, m, 5× Ph-H, furan-H), 7.21 (2H,d, 3′-H, 5′-H), 5.26 (2H, s, OCH₂); m/z (M+1)⁺ 423.

(4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

Reaction of(4-benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)amine (5.44 g,15.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (10.4 g, 24.2mmol) and bis(triphenylphosphine)palladium (II) chloride (catalyticamount) in dioxane (150 ml) according to Procedure B, followed bypurification by silica gel chromatography (eluted with 50-100%EtOAc/i-hexane), allowed the isolation of the dioxolane product (3.45 g,7.40 mmol, 49%); [²H₆]DMSO 10.28 (1H, s), 9.13 (1H, s), 8.69 (1H, s),8.61 (1H, s), 7.71 (2H, d), 7.31-7.52 (5H, m), 7.14 (1H, d), 7.09 (2H,d), 6.77 (1H, d), 6.03 (1H, s), 5.15 (2H, s), 3.95-4.19 (4H, m).

This could then be converted to5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde(identical to that described above) using Procedure C.

(4-Phenoxyphenyl)-(7-iodoquinolin-4-yl)amine

4-Chloro-7-iodoquinoline (10 g, 34 mmol) [Semenov, V. P.; Studenikov, A.N. Synthesis of 7-iodo-4-aminoquinoline derivatives. Khim. Geterotsikl.Soedin. (1980), Issue 7, 972-5] and 4-phenoxyaniline (6.38 g, 34 mmol)in butanol (75 ml) were heated at gentle reflux (120° C.) overnight (18hrs). On cooling the resultant precipitate was collected by filtrationand washed with acetonitrile (2×50 ml). The resultant solid wassuspended in chloroform (500 ml) and 2N sodium carbonate solution (300ml) and heated at 75° C. for 45 mins. On cooling the resultantprecipitate was collected by filtration, washed with water (2×50 ml) anddried to yield the product as a pale brown solid. (9.95 g, 66%) δH [²H₆]DMSO 8.35 (3H, m), 8.20 (1H, s), 8.10 (1H, d), 7.85 (1H, s), 7.35 (4H,m), 7.15 (4H, d), 6.75 (1H, d).

(4-Benzyloxyphenyl)-(6-bromoquinazolin-4-yl)-amine hydrochloride

4-Chloro-6-bromoquinazoline (0.25 g, 1.0 mmol) and 4-benzyloxyaniline(0.25 g, 1.3 mmol) were mixed in 2-propanol (6 ml) and heated at refluxfor 10 mins (Procedure A). The solution was allowed to cool at roomtemperature and the 2-propanol removed in vacuo. The resulting solid wastriturated with acetone to give the product as a yellow solid (0.39 g,88%); δH [²H₆]-DMSO 11.60 (1H, b, NH), 9.21 (1H, s, 5-H), 8.86 (1H, s,2-H), 8.20 (1H, d, 7-H), 7.90 (1H, d, 8-H), 7.65 (2H, d, 2′-H, 6′-H),7.50-7.25 (5H, m, Ph-H), 7.10 (2H, d, 3′-H, 5′-H), 5.15 (2H, s, CH₂);m/z 405/407 (M+).

(4-Benzyloxyphenyl)-(6-iodoquinazolin-4-yl)-amine hydrochloride

4-Chloro-6-iodoquinazoline (8 g) was treated with 4-benzyloxyaniline(5.5 g) in acetonitrile (500 ml) at reflux under N₂ for 18 hours.Subsequent cooling and filtration gave the title compound (13.13 g); δH[²H₆]-DMSO 11.45 (1H, b, NH), 9.22 (1H, s, 5-H), 8.89 (1H, s, 2-H), 8.36(1H, d, 7-H), 7.69 (1H, d, 8-H), 7.63 (2H, d, 2′-H, 6′-H), 7.52-7.29(5H, m, Ph-H), 7.14 (2H, d, 3′-H, 5′-H), 5.18 (2H, s, CH₂); m/z (M+1)⁺454.

(4-Benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride

Prepared according to Procedure A from4-chloro-6-iodo-7-fluoro-quinazoline hydrochloride (4.02 grams, 11.65mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml) and4-benzyloxyaniline hydrochloride (2.83 grams, 12 mmoles). The mixturewas stirred and heated to 110° C. (oil bath temperature) for 16 hours.The mixture was cooled to room temperature and filtered to remove theprecipitated solids. The solids were washed with cold anhydrous dioxane(100 ml) followed by cold anhydrous diethyl ether. The yellowish solidwas collected and dried under vacuum at room temperature to yield 4.68grams (79%) of the title compound. δH (400 MHz, DMSO-d₆): 11.2 (s, 1H),9.3 (d, 1H), 8.79 (s, 1H), 7.64 (d, 1H), 7.58 (d, 2H), 7.44 (d, 2H),7.38 (m, 2H), 7.31 (m, 1H), 7.09 (d, 2H), 5.14 (s, 2H) ESI-MS m/z 472(M+1).

(1-Benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride

Prepared according to Procedure A from 1-benzyl-1H-indazol-5-ylamine and4-chloro-6-iodo-7-fluoroquinazoline. δH (400 MHz, DMSO-d₆): 11.55 (s,1H), 9.41 (d, 1H), 8.8 (s, 1H), 8.18 (s, 1H), 8.05 (d, 1H), 7.78 (d,1H), 7.69 (d, 1H), 7.61 (m, 1H), 7.29 (m, 2H), 7.23 (m, 3H), 5.67 (s,2H). ESI-MS m/z 496 (M+1).

(4-Benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride

Prepared according to Procedure A from 4-(benzenesulphonyl)phenylamineand 4-chloro-6-iodo-7-fluoroquinazoline. ¹H NMR (400 MHz, DMSO-d₆) δ:10.89 (s, 1H), 9.3 (d, 1H), 8.79 (s, 1H), 8.07 (d, 2H), 8.0 (d, 2H),7.94 (d, 2H), 7.67 (m, 2H), 7.61 (m, 2H). ESI-MS m/z 504 (M−1).

6-Iodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-quinazolin-4yl)amine

Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-3-chlorophenyl)amine and4-chloro-6-iodo-quinazoline. ¹H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s,1H); 8.58 (s, 1H); 8.09 (d, 1H); 8.00 (d, 1H); 7.61 (d, 1H); 7.52 (d,1H); 7.44 (m, 1H); 7.20-7.33 (m, 3H); 7.15 (m, 1H); 5.21 (s, 2H); MS m/z506 (M+1).

6-Iodo-(4-(3-fluorobenzyloxy)-3-fluorophenyl)-quinazolin-4yl)amine

Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-3-fluorophenyl)amine and4-chloro-6-iodo-quinazoline. ¹H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s,1H); 8.57 (s, 1H); 8.08 (d, 1H); 7.85 (d, 1H); 7.53 (d, 1H); 7.50 (d,1H); 7.43 (m, 1H); 7.30-7.20 (m, 3H); 7.15 (m, 1H); 5.20 (s, 2H); MS m/z490 (M+1).

6-Iodo-(4-(3-fluorobenzyloxy)-3-methoxyphenyl)-quinazolin-4yl)amine

Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-3-methoxyphenyl)amine and4-chloro-6-iodo-quinazoline. ¹H NMR 400 MHz (DMSO-d6) 11.29 (bs, 1H0;9.14 (s, 1H); 8.87 (s, 1H); 8.32 (d, 1H); 7.62 (d, 1H); 7.42 (m, 1H);7.34 (d, 1H); 7.29-7.22 (m, 3H); 7.18-7.08 (m, 2H); 5.15 (s, 2H); 3.80(s, 3H); MS m/z 502 (M+1)

6-Iodo-(4-benzyloxy-3-fluorophenyl)-quinazolin-4-yl)amine

Prepared according to Procedure A from 4-benzyloxy)-3-fluorophenylamineand 4-chloro-6-iodo-quinazoline. ¹H NMR (DMSO-d6) 9.82 (s, 1H); 8.93 (s,1H); 8.57 (s, 1H); 8.09 (d, 1H); 7.84 (d, 1H); 7.51 (m, 2H); 7.44 (d,2H); 7.37 (m, 2H); 7.33 (m, 1H); 7.24 (m, 1H); 5.18 (s, 2H); MS m/z 472(M+1)

6-Iodo-(4-(3-bromobenzyloxy)-phenyl)-quinazolin-4-yl)amine

Prepared according to Procedure A from(4-(3-bromobenzyloxy)-phenyl)amine and 4-chloro-6-iodo-quinazoline. ¹HNMR (DMSO-d6) 9.84 (s, 1H); 8.98 (s, 1H); 8.57 (s, 1H); 8.13 (m, 2H);7.71 (d, 2H); 7.56 (d, 2H); 7.50 (m, 1H); 7.41 (m, 1H); 7.08 (d, 2H);5.17 (s, 2H).

6-Iodo-(4-(3-fluorobenzyloxy)-phenyl)-quinazolin-4-yl)amine

Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-phenyl)amine and 4-chloro-6-iodo-quinazoline. ¹HNMR (DMSO-d6) 9.77 (s, 1H); 8.92 (s, 1H); 8.50 (s, 1H); 8.06 (d, 1H);7.66 (d, 2H); 7.50 (d, 1H); 7.42 (m, 1H); 7.30-7.25 (m, 2H); 7.14 (m,1H); 7.03 (d, 2H); 5.13 (s, 2H); MS m/z 472 (M+1)

6-Iodo-(4-(3-trifluoromethylbenzyloxy)-phenyl)-quinazolin-4-yl)amine

Prepared according to Procedure A from(4-(3-trifluoromethylbenzyloxy)-phenyl)amine and4-chloro-6-iodo-quinazoline. ¹H NMR (DMSO-d6) 9.2 (bs, 1H); 8.91 (s,1H); 8.37 (d, 1H); 7.89-7.72 (m, 8H); 7.19 (d, 2H); 5.30 (s, 2H).

6-Iodo-(4-benzyloxy-3-trifluoromethyl-phenyl)-quinazolin-4-yl)amine

The mixture of 4-chloro-6-iodo-quinazoline (366 mg, 1.26 mmol) and4-O-benzyl-3-trifluoroaniline (405 mg, 1.26 mmol) in isopropanol (12 ml)was heated to reflux for 3.5 hours. Filtered, washed with isopropanoland dried. 535 mg yellow solid was afforded. (yield: 76%). ESI-MS m/z522 (M+H)⁺.

(4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine

Synthesized according to Procedure B from a solution of(4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride (508 mg, 1 mmole),5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole),diisopropylethyl amine (650 mg, 5 mmole), anddichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6 ml ofDMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4hours. The cooled reaction mixture was extracted with water (100 ml) andethyl acetate (100 ml). The organic phase was washed with brine (100ml). The aqueous layers were combined and washed with additional ethylacetate (100 ml). The organic layers were combined, dried with MgSO₄,filtered and concentrated to a residue. The residue was chromatographedon silica gel with a methanol-chloroform mixture. Fractions werecollected, combined, and concentrated. The resultant solid was suspendedin dichloromethane (10 ml) and diethyl ether was added facilitateprecipitation. The solid was filtered and dried under vacuum at roomtemperature to yield a yellowish solid 287 mg (59%). ¹H NMR (400 MHz,DMSO-d₆) δ: 10.1 (s, 1H), 8.85 (d, 1H), 8.45 (s, 1H), 7.6 (m, 3H), 7.44(d, 2H), 7.38 (m, 2H), 7.31 (m, 1H), 7.03 (m, 2H), 6.94 (m, 1H), 6.74(d, 1H), 6.01 (s, 1H), 5.1 (s, 2H), 4.10 (m, 2H), 3.96 (m, 2H). ESI-MSm/z 482 (M−1).

(1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine

Prepared according to Procedure B from(1-benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ ¹HNMR (400 MHz, DMSO-d₆) δ 10.27 (s, 1H), 8.89 (d, 1H), 8.46 (s, 1H), 8.1(d, 2H), 7.69 (d, 1H), 7.61 (m, 2H), 7.26 (m, 5H), 6.96 (m, 1H), 6.74(d, 1H), 6.01 (s, 1H), 5.65 (s, 2H), 4.09 (m, 2H), 3.96 (m, 2H). ESI-MSm/z 506 (M−1).

(4-Benzenesulphonyl)phenyl-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine

Prepared according to Procedure B from(4-benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ¹HNMR (400 MHz, DMSO-d₆) 10.49 (s, 1H), 8.88 (d, 1H), 8.63 (s, 1H), 8.1(d, 2H), 7.95 (m, 4H), 7.65 (m, 4H), 6.97 (m, 1H), 6.75 (d, 1H), 6.01(s, 1H), 4.09 (m, 2H), 3.97 (m, 2H). ESI-MS m/z 516 (M−1).

(4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine

Prepared according to Procedure B from(4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (1.5 g, 3.7 mmol)and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (1.9 g, 4.42 mmol)dissolved in dioxan (30 ml) and heated at reflux under nitrogen for 6hr. The solvent was removed from the cooled reaction under vacuum, andthe residual oil was triturated with iso-hexane/ethyl acetate to givethe product (1.07 g, 62%) as a pale yellow solid; 6H [²H₆]-DMSO 9.96(1H, b, NH), 8.80 (1H, s, 5-H), 8.51 (1H, s, 2-H), 8.18 (1H, d, 7-H),7.80 (1H, d, 8-H), 7.70 (2H, d, 2′-H, 6′-H), 7.58-7.30 (5H, m, 5×Ph-H),7.10 (3H, m, 3′-H, 5′-H, furan 3-H), 6.78 (1H, d, furan 4-H), 6.12 (1H,s, CHO₂), 5.18 (2H, s, PhCH ₂), 4.22-3.94 (4H, m, 2×CH₂); m/z 466(M+1)⁺.

(4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine

Prepared according to Procedure B using6-Iodo-(4-benzyloxy-3-trifluoromethyl-phenyl)-quinazolin-4-yl)amine (480mg, 0.92 mmol), and 5-tributyltin-(1,3-dioxolan-2-yl)-furan (731 mg,1.38 mmol) in dioxane (10 ml). The resulting product was a yellow solid(0.47 g, 95.8% yield). ESI-MS m/z 534 (M+H)⁺.

5-(4-(4-Benzyloxy-3-trifluoromethylphenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde

Prepared according to Procedure C using(4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine(470 mg, 0.88 mmol) solution in THF (5 ml) followed by the addition of2N HCl (20 ml) at room temperature. The resulting mixture was stirredfor 30 minutes. Water was added (15 ml) then filtered. The yellow solidwas washed with water and small amount of ether and dried in vacuo (0.39g, 84% yield). ESI-MS m/z 490 (M+H)⁺.

(4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl)-amine

Prepared according to Procedure B from a solution of(4-benzyloxyphenyl)-7-methoxy-6-trifluoromethanesulphonyl-quinazolin-4-yl)-amine(0.30 g, 0.59 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan(0.37 g, 0.86 mmol), lithium chloride (78 mg, 1.8 mmol), anddichloro-bis(triphenylphosphine)palladium (90 mg, 0.13 mmol) in 2 ml ofDMF under nitrogen was stirred at 85-90° C. for 50 minutes. The cooledreaction mixture was partitioned between 30 ml of water and 40 ml ofethyl acetate. The organic solution was washed with 30 ml of brine,dried with Na₂SO₄ and concentrated in vacuo. The residue waschromatographed on silica gel with hexanes/ethyl acetate (1:1 to 0:1).The resulting solution was concentrated to near dryness and theresulting solid suspended in ether and filtered to give 0.232 g ofproduct as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.90 (s,1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.60 (d, 2H), 7.44 (d, 2H), 7.37 (t,2H), 7.30 (t, 1H), 7.24 (s, 1H), 7.00 (m, 3H), 6.67 (d, 1H), 5.99 (s,1H), 5.09 (s, 2H), 4.10 (m, 2H), 4.02 (s, 3H), 3.95 (m, 2H). ESI-MS m/z496 (M+1).

(4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine

Prepared according to Procedure B from a solution of(4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride (508 mg, 1 mmole),5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole),diisopropylethyl amine (650 mg, 5 mmole), anddichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6 ml ofDMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4hours. The cooled reaction mixture was extracted with water (100 ml) andethyl acetate (100 ml). The organic phase was washed with brine (100ml). The aqueous layers were combined and washed with additional ethylacetate (100 ml). The organic layers were combined, dried with MgSO₄,filtered and concentrated to a residue. The residue was chromatographedon silica gel with a methanol-chloroform mixture. Fractions werecollected, combined, and concentrated. The resultant solid was suspendedin dichloromethane (10 ml) and diethyl ether was added to facilitateprecipitation. The solid was filtered and dried under vacuum at roomtemperature to yield a yellow solid 287 mg (59%). ¹H NMR (400 MHz,DMSO-d₆) δ: 10.1 (s, 1H), 8.85 (d, 1H), 8.45 (s, 1H), 7.6 (m, 3H), 7.44(d, 2H), 7.38 (m, 2H), 7.31 (m, 1H), 7.03 (m, 2H), 6.94 (m, 1H), 6.74(d, 1H), 6.01 (s, 1H), 5.1 (s, 2H), 4.10 (m, 2H), 3.96 (m, 2H). ESI-MSm/z 482 (M−1).

(4-Benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride

Prepared according to Procedure A from4-chloro-6-iodo-7-fluoro-quinazoline hydrochloride (4.02 grams, 11.65mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml), and4-benzyloxyaniline hydrochloride (2.83 grams, 12 mmoles). The mixturewas stirred and heated to 110° C. (oil bath temperature) for 16 hours,cooled to room temperature and filtered to remove the precipitatedsolids. The solids were washed with cold anhydrous dioxane (100 ml)followed by cold anhydrous diethyl ether. The yellowish solid wascollected and dried under vacuum at room temperature to yield 4.68 grams(79%) of the title compound. δH NMR (400 MHz, DMSO-d₆): 11.2 (s, 1H),9.3 (d, 1H), 8.79 (s, 1H), 7.64 (d, 1H), 7.58 (d, 2H), 7.44 (d, 2H),7.38 (m, 2H), 7.31 (m, 1H), 7.09 (d, 2H), 5.14 (s, 2H) ESI-MS m/z 472(M+1).

(1-Benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride

Prepared according to Procedure A from 1-benzyl-1H-indazol-5-ylamine and4-chloro-6-iodo-7-fluoroquinazoline. δH NMR (400 MHz, DMSO-d₆): 11.55(s, 1H), 9.41 (d, 1H), 8.8 (s, 1H), 8.18 (s, 1H), 8.05 (d, 1H), 7.78 (d,1H), 7.69 (d, 1H), 7.61 (m, 1H), 7.29 (m, 2H), 7.23 (m, 3H), 5.67 (s,2H). ESI-MS m/z 496 (M+1).

(4-Benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-aminehydrochloride

Prepared according to Procedure A from 4-benzenesulphonyl)phenylamineand 4-chloro-6-iodo-7-fluoroquinazoline. δHNMR (400 MHz, DMSO-d₆) δ:10.89 (s, 1H), 9.3 (d, 1H), 8.79 (s, 1H), 8.07 (d, 2H), 8.0 (d, 2H),7.94 (d, 2H), 7.67 (m, 2H), 7.61 (m, 2H). ESI-MS m/z 504 (M−1).

6-Iodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-quinazolin-4yl)amine

Prepared according to Procedure A from4-(3-fluorobenzyloxy)-3-chlorophenyl)-amine and4-chloro-6-iodoquinazoline. ¹H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s, 1H);8.58 (s, 1H); 8.09 (d, 1H); 8.00 (d, 1H); 7.61 (d, 1H); 7.52 (d, 1H);7.44 (m, 1H); 7.20-7.33 (m, 3H); 7.15 (m, 1H); 5.21 (s, 2H); MS m/z 506(M+1)

6-Iodo-(4-(3-fluorobenzyloxy)-3-fluorophenyl)-quinazolin-4yl)amine

Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-3-fluorophenyl)-amine and4-chloro-6-iodoquinazoline. ¹H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s, 1H);8.57 (s, 1H); 8.08 (d, 1H); 7.85 (d, 1H); 7.53 (d, 1H); 7.50 (d, 1H);7.43 (m, 1H); 7.30-7.20 (m, 3H); 7.15 (m, 1H); 5.20 (s, 2H); MS m/z 490(M+1)

6-Iodo-(4-(3-fluorobenzyloxy)-3-methoxyphenyl)-quinazolin-4yl)amine

Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-3-fluorophenyl)-amine and4-chloro-6-iodoquinazoline. ¹H NMR 400 MHz (DMSO-d6) 11.29 (bs, 1H0;9.14 (s, 1H); 8.87 (s, 1H); 8.32 (d, 1H); 7.62 (d, 1H); 7.42 (m, 1H);7.34 (d, 1H); 7.29-7.22 (m, 3H); 7.18-7.08 (m, 2H); 5.15 (s, 2H); 3.80(s, 3H); MS m/z 502 (M+1)

6-Iodo-(4-benzyloxy-3-fluorophenyl)-quinazolin-4-yl)amine

Prepared according to Procedure A from(4-benzyloxy-3-fluorophenyl)-amine and 4-chloro-6-iodoquinazoline. ¹HNMR (DMSO-d6) 9.82 (s, 1H); 8.93 (s, 1H); 8.57 (s, 1H); 8.09 (d, 1H);7.84 (d, 1H); 7.51 (m, 2H); 7.44 (d, 2H); 7.37 (m, 2H); 7.33 (m, 1H);7.24 (m, 1H); 5.18 (s, 2H), MS m/z 472 (M+1)

6-Iodo-(4-(3-bromobenzyloxy)-phenyl)-quinazolin-4-yl)amine

Prepared according to Procedure A from(4-(3-bromobenzyloxy)-phenyl)-amine and 4-chloro-6-iodoquinazoline. ¹HNMR (DMSO-d6) 9.84 (s, 1H); 8.98 (s, 1H); 8.57 (s, 1H); 8.13 (m, 2H);7.71 (d, 2H); 7.56 (d, 2H); 7.50 (m, 1H); 7.41 (m, 1H); 7.08 (d, 2H);5.17 (s, 2H).

6-Iodo-(4-(3-fluorobenzyloxy)-phenyl)-quinazolin-4-yl)amine

Prepared according to Procedure A from(4-(3-fluorobenzyloxy)-phenyl)-amine and 4-chloro-6-iodoquinazoline. ¹HNMR (DMSO-d6) 9.77 (s, 1H); 8.92 (s, 1H); 8.50 (s, 1H); 8.06 (d, 1H);7.66 (d, 2H); 7.50 (d, 1H); 7.42 (m, 1H); 7.30-7.25 (m, 2H); 7.14 (m,1H); 7.03 (d, 2H); 5.13 (s, 2H), MS m/z 472 (M+1)

6-Iodo-(4-(3-trifluoromethylbenzyloxy)-phenyl)-quinazolin-4-yl)amine

Prepared according to Procedure A from(4-(3-trifluoromethylbenzyloxy)-phenyl)-amine and4-chloro-6-iodoquinazoline. ¹H NMR (DMSO-d6) 9.2 (bs, 1H); 8.91 (s, 1H);8.37 (d, 1H); 7.89-7.72 (m, 8H); 7.19 (d, 2H); 5.30 (s, 2H).

4-(4-(4-Phenoxyphenylamino)-quinolin-7-yl) thiazole-2-carbaldehyde

Prepared according to Procedure B from(4-phenoxyphenyl)-(7-iodoquinolin-4-yl)amine (2 g, 4.56 mmol),4-(tributylstannyl)thiazole-2-carbaldehyde (1.84 g, 4.56 mmol) anddichlorobis(triphenylphosphine)palladium (II) (0.74 g, 20 mol %) heatedat reflux overnight (18 hrs) in dioxane (50 ml). The cooled solution wasfiltered through a plug of Celite®, concentrated and triturated withiso-hexane (3×20 ml). The resultant solid was purified via flash columnchromatography on silica gel, eluting with 5% methanol in chloroform.The purified product was isolated as a yellow solid (0.85 g, 44%). δH[²H₆] DMSO 10.10 (1H, s), 9.30 (1, bs), 8.90 (1 Hs), 8.50 (2H, s&d),8.45 (1H, d), 8.20 (1H, d), 7.40 (5H, bm), 7.10 (4H, 2d), 6.80 (1H, d).

5-(4-(4-Phenoxyphenylamino)-quinolin-7-yl) thiazole-4-carbaldehyde

Prepared according to Procedure B from(4-phenoxyphenyl)-(7-iodoquinolin-4-yl)amine (0.876 g, 2 mmol),4-(1,3-dioxolan-2-yl)-5-tributylstannylthiazole (2.1 mmol),bis(triphenylphosphine) palladium (II) chloride (0.105 g, 0.15 mmol, 7.5mol %) and silver oxide (0.463 g, 2 mmol) heated under reflux undernitrogen for 18 hr. The reaction mixture was then filtered throughHarborlite® and the filtrate was concentrated. The product was purifiedon Bond Elut™ cartridge, eluting sequentially with dichloromethane,chloroform, diethyl ether and ethyl acetate. The ketal (0.385 g, 0.824mmol) was stirred at room temperature in a mixture of THF (10 ml) and 1NHCl (10 ml) for 2 hr. The suspension was basified with 2N NaOH (5 ml)and the THF was removed. The aqueous suspension was filtered and washedwith water to give the product as a yellow solid (0.346 g); m/z 424.

5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde

Prepared according to Procedure C from4-(4-benzyloxy-phenylamino)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine(1.0 g, 2.1 mmol). The precipitate which formed was collected byfiltration and washed with acetone, then partitioned between ethylacetate, triethylamine and water. The organic phase was washed withwater, dried (magnesium sulphate) and the solvent was removed undervacuum. Trituration with iso-hexane/ethyl acetate gave the product as anorange solid (610 mg, 69%); δH [²H₆]-DMSO 10.05 (1H, b, NH), 9.62 (1H,s, CHO), 8.95 (1H, s, 5-H), 8.48 (1H, s, 2-H), 8.24 (1H, d, 7-H), 7.80(1H, d, 8-H), 7.70 (1H, d, furan 4-H), 7.59 (2H, d, 2′-H, 6′-H),7.48-7.25 (6H, m, 5×Ph-H, furan 3-H), 7.02 (2H, m, 3′-H, 5′-H), 5.09(2H, s, CH₂); m/z 422 (M+1)⁺.

5-(4-(4-Benzyloxy-phenylamino)-7-methoxy-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride

Prepared according to Procedure C from(4-benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-pyrido[3,4-d]pyrimidin-4-yl)-amine(0.301 g, 0.60 mmol). After stirring 45 minutes, the resultingsuspension was filtered and washed with ether to give 0.26 g of productas a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.67 (br s, 1H), 9.68(s, 1H), 9.14 (s, 1H), 8.78 (s, 1H), 7.73 (d, 1H), 7.52 (d, 2H), 7.44(m, 3H), 7.39 (m, 3H), 7.32 (m, 1H), 7.11 (d, 2H), 5.14 (s, 2H), 4.12(s, 3H). ESI-MS m/z 452 (M+1).

6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl-(4-benzenesulphonyl)phenyl-amine

Prepared according to Procedure B from4-(4-benzenesulphonyl)phenyl-7-methoxy-quinazolin-4-yl-amine and5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ¹H NMR (400 MHz,DMSO-d₆) 10.36 (s, 1H), 8.74 (s, 1H), 8.58 (s, 1H), 8.10 (d, 2H), 7.93(m, 4H), 7.62 (m, 3H), 7.32 (s, 1H), 7.04 (d, 1H), 6.68 (d, 1H), 5.99(s, 1H), 4.09 (m, 2H), 4.04 (s, 3H), 3.95 (m, 2H). ESI-MS m/z 530 (M+1).

5-(4-(4-Phenoxyphenylamino)-quinolin-7-yl)furan-2-carbaldehyde

(4-Phenoxyphenyl)-(7-(5-(1,3-dioxolan-2-yl)furan-2-yl)-quinolin-4-yl)amine(1.4 g) was treated with 1M aqueous hydrochloric acid-tetrahydrofuran(60 ml, 1:1) in accordance with procedure C. Addition of 1M aqueoussodium hydroxide solution to pH 10 followed by extraction with ethylacetate, drying (magnesium sulfate) and concentration to drynessafforded a yellow solid (1.2 g); δH [²H₆] DMSO 9.70 (1H, s), 9.10 (1H,s), 8.51 (2H, m), 8.35 (1H, s), 8.02 (1H, d), 7.73 (1H, d), 7.57 (1H,d), 7.42 (4H, m), 7.22-7.04 (5H, m), 6.88 (1H, d); m/z 407 (M+1)⁺.

5-(7-Methoxy-4-(4-benzenesulphonyl)phenylamino-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride

Prepared according to Procedure C from6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl-(4-benzenesulphonyl)phenyl-amine.δ¹H NMR (400 MHz, DMSO-d₆) 11.54 (br s, 1H), 9.68 (s, 1H), 9.13 (s, 1H),8.83 (s, 1H), 7.95-8.06 (m, δH), 7.72 (d, 1H), 7.68 (m, 1H), 7.62 (m,2H), 7.46 (s, 1H), 7.39 (d, 1H), 4.12 (s, 3H). ESI-MS m/z 486 (M+1).

5-(4-(4-Benzyloxy-phenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carboxaldehydehydrochloride

Prepared according to Procedure C from a stirred solution of(4-benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine(0.51 grams, 1.1 mmol) in 20 ml of THF was added 5 ml of 1 N HCl. Afterstirring for 90 minutes, the resultant suspension was filtered andwashed with diethyl ether (200 ml) to yield, after drying under vacuum,a yellow solid (0.32 grams, 61% yield). δ¹H NMR (400 MHz, DMSO-d₆) 11.52(s, 1H), 9.70 (s, 1H), 9.25 (d, 1H), 8.76 (s, 1H), 7.76 (m, 2H), 7.55(d, 2H), 7.45 (d, 2H), 7.33 (m, 4H), 7.11 (d, 2H), 5.14 (s, 2H). ESI-MSm/z 440 (M+1).

5-(4-(1-Benzyl-1H-indazol-5-ylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride

Prepared according to Procedure C from(1-benzyl-1H-indazol-5-ylamino)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine.δ¹H NMR (400 MHz, DMSO-d₆) 11.68 (s, 1H), 9.71 (s, 1H), 9.28 (d, 1H),8.74 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.78 (m, 3H), 7.58 (m, 2H),7.3 (m, 5H), 5.65 (s, 2H). ESI-MS m/z 462 (M−1).

5-(4-(4-Benzenesulphonylphenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride

Prepared according to Procedure C from6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl-(4-benzenesulphonyl)phenyl-amine.¹H NMR (400 MHz, DMSO-d₆) δ: 10.96 (s, 1H), 9.7 (s, 1H), 9.16 (d, 1H),8.72 (s, 1H), 8.07 (d, 2H), 7.96 (m, 4H), 7.75 (m, 2H), 7.64 (m, 3H),7.29 (m, 1H. ESI-MS m/z 472 (M−1).

5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride

Prepared according to Procedure C from4-(4-benzyloxyphenylamino)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine(6.70 g, 14.4 mmol). The resulting precipitate was collected byfiltration and washed with water to give the hydrochloride salt as ayellow solid (6.50 g, 14.1 mmol, 98%); δH [²H₆]DMSO 12.15 (1H, s), 9.69(1H, s) 9.58 (1H, s), 8.88 (1H, s), 8.50 (1H, dd), 8.02 (1H, d), 7.77(1H, d), 7.62-7.74 (3H, m), 7.31-7.52 (5H, m), 7.15 (2H, d), 5.17 (2H,s).

(4-Phenoxyphenyl)-(7-(5-(1,3-dioxolan-2-yl)furan-2-yl)-quinolin-4-yl)amine

(4-Phenoxyphenyl)-(7-iodo-quinolin-4-yl)amine (2 g) was treated with2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (2.16 g) andtetrakis(triphenylphosphine) palladium (0) (0.26 g) in dimethylacetamide(20 ml) in accordance with Procedure B. Purification via columnchromatography, eluting with ethyl acetate, followed by trituration withdiethylether afforded a yellow solid (1.4 g); δH [²H₆] DMSO 9.10 (1H,s), 8.45 (2H, m), 8.13 (1H, s), 7.96 (1H, d), 7.41 (4H, m), 7.22 (1H,d), 7.20-7.03 (5H, m), 6.83 (1H, d), 6.75 (1H, d), 6.02 (1H, s), 4.13(2H, m), 4.01 (2H, m); m/z 451 (M+1)⁺.

(1-Benzyl-1H-indazol-5-yl)-(6-bromoquinazolin-4-yl)-amine

Prepared according to Procedure A from 6-bromo-4-chloroquinazoline (5.0g) and 5-amino-1-benzyl-1H-indazole (5.0 g) in acetonitrile (100 ml) at100° C. The resulting precipitate was treated with triethylamine inethyl acetate and water to give the title compound as a yellow solid,(7.37 g); δH [²H₆]-DMSO 9.93 (1H, s), 8.82 (1H, d), 8.52 (1H, s), 8.19(1H, s), 8.09 (1H, s), 7.92 (1H, dd), 7.65 (3H, m), 7.25 (5H, m), 5.62(2H, s).

(1-Benzyl-1H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amine hydrochloride

Prepared according to Procedure A from 4-chloro-6-iodoquinazoline (5.8g) was treated with 5-amino-1-benzyl-1H-indazole (3.90 g) inacetonitrile (500 ml) at reflux under N₂ for 18 hours. Subsequentcooling and filtration gave the title compound (8.26 g); m/z (M+1)⁺ 478.

(1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine

Prepared according to Procedure B from(1-benzyl-1H-indazol-5-yl)-(6-bromoquinazolin-4-yl)-amine (4.3 g),2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)furan (J. Chem. Soc., ChemCommun., (1988), 560) (10 g) and 1,4-bis(diphenylphosphino) palladium(II) chloride (1 g) in dioxane. The solvent was removed in vacuo and theresidue chromatographed on silica. Subsequent trituration gave the titlecompound δH [²H₆]-DMSO 10.13 (1H, s), 8.85 (1H, s), 8.54 (1H, s), 8.20(3H, m), 7.80 (3H, m), 7.30 (5H, m), 7.13 (1H, d), 6.79 (1H, d), 6.04(1H, s), 5.71 (2H, s), 4.15 (4H, m).

(1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl)-amine

Prepared according to Procedure B from(1-benzyl-1H-indazol-5-yl)-7-methoxy-6-trifluoromethanesulphonyl-quinazolin-4-yl)-amineand 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan. ¹H NMR (400 MHz,DMSO-d₆) δ: 10.07 (s, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 8.09 (s, 2H),7.64 (m, 2H), 7.2-7.3 (m, 6H), 7.01 (d, 1H), 6.68 (d, 1H), 5.99 (s, 1H),5.64 (s, 2H), 4.09 (m, 2H), 4.03 (s, 3H), 3.94 (m, 2H). ESI-MS m/z 520(M+1).

5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride

Prepared according to Procedure C from(1-benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine(2.0 g). The resulting precipitate was filtered, washed with water anddried at 60° C. in vacuo to give the product as a yellow solid (1.80 g,3.73 g, 91%); δH [²H₆]-DMSO 12.30 (1H, s), 9.79 (1H, s), 9.62 (1H, s),8.85 (1H, s), 8.62 (1H, m), 8.31 (1H, s), 8.19 (1H, m), 8.10 (1H, d),7.90 (2H, m), 7.78 (2H, m), 7.40 (5H, m), 5.80 (2H, s).

5-(4-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride

Prepared according to Procedure C from(1-benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl)-amine.δH NMR (400 MHz, DMSO-d₆): 11.94 (br s, 1H), 9.68 (s, 1H), 9.20 (s, 1H),8.79 (s, 1H), 8.19 (s, 1H), 7.97 (d, 1H), 7.81 (d, 1H), 7.74 (d, 1H),7.57 (m, 1H), 7.44 (s, 1H), 7.41 (d, 1H), 7.30 (m, 2H), 7.24 (m, 3H),5.68 (s, 2H), 4.13 (s, 3H). ESI-MS m/z 476 (M+1).

7-Iodoquinazolin-4-one

7-Amino-quinazolin-4-one (R. Dempsy and E. Skito, Biochemistry, 30,1991, 8480) (1.61 g) was suspended in 6N HCl (20 ml) and cooled in anice bath. A solution of sodium nitrite (0.75 g) in water (10 ml) wasadded dropwise over 15 minutes. After a further 10 minutes, a solutionof potassium iodide (1.66 g) in water (5 ml) was added dropwise. Themixture was warmed to 20° C. and after 3 hours partitioned between ethylacetate and sodium thiosulphate. The organic phase was dried andconcentrated in vacuo to give the title compound (0.485 g); m/z (M+1+)271.

4-Chloro-7-iodoquinazoline

7-Iodoquinazolin-4-one (0.46 g) was treated with phosphorous oxychloride(5 ml) at reflux under nitrogen for 2 hours. The mixture was cooled,evaporated and partitioned between saturated aqueous sodium carbonateand ethyl acetate. The organic phase was dried and concentrated in vacuoto give the title compound (0.43 g); m/z (M+1+) 291.

(1-Benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amine hydrochloride

Prepared according to Procedure A from 4-Chloro-7-iodoquinazoline (0.42g) and 1-benzyl-1H-indazol-5-ylamine (0.323 g) in acetonitrile (20 ml)at reflux under nitrogen for 18 hours. The mixture was cooled andfiltered to give the title compound (0.57 g); m/z (M+1+) 478.

(1-Benzyl-1H-indazol-5-yl)-[7-(5-(1,3-dioxolan-2-yl)-furan-2-yl)quinazolin-4-yl]aminehydrochloride

Prepared according to Procedure B from(1-benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amine hydrochlorideand 5-(1,3-dioxolan-2-yl)-2-(tri-n-butylstannyl)furan; tlc Rf, 0.25(100% EtOAc on silica); m/z (M+1+) 490.

5-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde

Prepared according to Procedure C from(1-benzyl-1H-indazol-5-yl)-[7-(5-(1,3-dioxolan-2-yl)furan-2-yl)quinazolin-4-yl]-aminehydrochloride (0.27 g) stirred in THF:2N HCl (2:1, 15 ml) at 20° C. for1 hour. Filtration gave5-[4-(1-benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde,which was not further characterised.

(4-Benzyloxy-phenyl)-(6-((5-(2-methylthio-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-aminedihydrochloride

5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde(100 mg) and (methylthio)ethylamine (80 mg) in dichloromethane (5 ml)were reacted together as in Procedure D. Purification using columnchromatography, followed by conversion to the hydrochloride salt gave ayellow solid (61 mg). m/z 497 (M+1)⁺.

(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine

4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and4-(4-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) werereacted together as in Procedure A. The product was collected byfiltration as a yellow solid (1.83 g); m/z 381 (M+1)⁺.

(6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine

(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine(1.82 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (3.75 g) indioxan (40 ml) were reacted together as in Procedure B. The mixture wasevaporated and the residue suspended in dichloromethane. This was thenfiltered through celite and the solvent evaporated. The gummy residuewas then triturated with hexane giving a beige solid (1.21 g); m/z 485(M+1)⁺.

5-(4-(4-(4-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde

(6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine(500 mg) was treated with acid as in Procedure C. The product wascollected by filtration as a red solid (330 mg); m/z 441 (M+1)⁺.

(4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

5-(4-(4-(4-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (110 mg) and (methylthio)ethylamine (0.06 ml) indichloromethane (5 ml) were reacted together as in Procedure D.Purification using a Bond Elut™ cartridge gave a yellow oil (52 mg); m/z516 (M+1)⁺.

(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine

4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and4-(3-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) werereacted together as in Procedure A. The product was collected byfiltration as a yellow solid (1.86 g); m/z 381 (M+1)⁺.

(6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine

(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine(1.85 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (3.82 g) indioxan (40 ml) were reacted together as in Procedure B. The mixture wasevaporated and the residue suspended in dichloromethane. This was thenfiltered through Celite® and the solvent evaporated. The gummy residuewas then triturated with hexane giving a beige solid (1.74 g); m/z 485(M+1)⁺.

5-(4-(4-(3-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-3-carbaldehyde

(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine(1 g) and 5-(tributylstannyl)-furan-3-carbaldehyde (J. Org. Chem.(1992), 57(11), 3126-31) (1.84 g) in dioxan (35 ml) were reactedtogether as in Procedure B. The solvent was evaporated and the residuesuspended in dichloromethane. The mixture was filtered through Celite®and then evaporated. The residue was triturated with hexane giving abeige solid (1 g); m/z 441 (M+1)⁺.

5-(4-(4-(3-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde

(6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine(500 mg) was treated with acid as in Procedure C. The product wascollected by filtration as a beige solid (251 mg); m/z 441 (M+1)⁺.

(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

(5-(4-(4-(3-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde(125 mg) and (methylthio)ethylamine (0.08 ml) in dichloromethane (5 ml)were reacted together as in Procedure D. Purification using a Bond Elut™cartridge gave a yellow oil (80 mg); m/z 516 (M+1)⁺.

(4-Benzenesulphonyl-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine

Prepared according to Procedure A from 4-benzenesulphonylaniline (Helv.Chim. Acta., 1983, 66 (4), 1046) and4,6-dichloropyrido[3,4-d]pyrimidine; [²H₆]-DMSO 9.09 (1H, s), 8.80-8.88(2H, m), 8.19 (2H, d), 7.94-8.09 (4H, m), 7.53-7.20 (3H, m); m/z (M+1)⁺397.

(4-Benzenesulphonyl-phenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

(4-Benzenesulphonyl-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine(3.67 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (6.9 g)were reacted together in dioxan (100 ml) as in Procedure B. Purificationby column chromatography gave a cream solid (2.59 g); [²H₆]DMSO 10.6(1H, s) 9.26 (1H, s) 8.82 (1H, s) 8.78 (1H, s) 8.25 (2H, d) 8.0-8.3 (4H,d+m) 7.65-7.8 (3H, m) 7.21 (1H, d) 6.82 (1H, d) 6.09 (1H, s) 4.0-4.2(4H, m); m/z 501 (M+1)⁺.

5-(4-(4-Benzenesulphonyl-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)furan-2-carbaldehydehydrochloride

(4-Benzenesulphonyl-phenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(2.59 g) was treated with acid in tetrahydrofuran (70 ml) as inProcedure C. The compound was obtained as a yellow solid afterfiltration (1.57 g);

[²H₆]DMSO 9.7 (1H, s) 9.26 (1H, s) 9.11 (1H, s) 8.82 (1H, s) 8.19 (1H,s) 8.15 (1H, s) 7.95-8.03 (4H, m) 7.75 (1H, d) 7.58-7.7 (3H, m) 7.49(1H, s); m/z 457

(4-Benzenesulphonyl-phenyl)-(6-(2-((2-methylthio-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-aminedihydrochloride

5-(4-((4-Benzenesulphonyl-phenyl)amino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde(250 mg) and (methylthio)ethylamine (185 mg)) in dichloromethane (5 ml)were reacted together as in Procedure D. Purification using a Bond Elut™cartridge, gave a yellow solid (245 mg), 70 mg of which was converted tothe hydrochloride salt, (yellow solid, 68 mg); m/z 532 (M+1)⁺.

(4-Benzyloxy-phenyl)-(6-(3-(1,3-dioxolan-2-yl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine

(4-Benzyloxy-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (1.4g) and 3-(1,3-dioxolan-2-yl)-phenyl-tributylstannane (3.08 g) [A. Leeand W-C. Dai, Tetrahedron (1997), 53(3), 859-868] in dioxan (30 ml) werereacted together as in Procedure B. The mixture was evaporated and theresidue suspended in dichloromethane. This was then filtered throughcelite and the solvent evaporated. The gummy residue was then trituratedwith hexane giving a beige solid. This material was further purified bycolumn chromatography, giving a brown foam (252 mg); m/z 477 (M+1)⁺.

3-(4-((4-Benzyloxy-phenyl)-amino)-pyrido[3,4-d]pyrimidin-6-yl)-benzaldehyde

(4-(4-Benzyloxy-phenyl)-6-(3-(1,3-dioxolan-2-yl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(250 mg) was treated with acid as in Procedure C. The product wasisolated by filtration as a brown solid (115 mg); m/z 433 (M+1)⁺.

4-(4-(4-Benzyloxy-phenyl)-amino)-quinazolin-6-yl)-thiazol-2-carbaldehyde

(4-Benzyloxy-phenyl)-(6-iodo-quinazolin-4-yl)-amine (2 g) and4-(tributylstannyl)-thiazol-2-carbaldehyde (3.28 g) in dioxan (25 ml)were reacted together as in Procedure B. The mixture was evaporated andthe residue purified using column chromatography, giving a yellow solid(849 mg); m/z 439 (M+1)⁺.

Other suitable intermediates prepared by analogous methods to thosedescribed above are:

-   (4-Benzyloxy-3-chlorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-trifluoromethylphenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-bromophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-bromophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-iodophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-iodophenyl)-6-(chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-3-fluorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluoro-benzyloxy-3-fluorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   5-((4-Benzyloxy-3-chlorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;-   5-((4-(3-Fluoro-benzyloxy)-3-chlorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;-   5-((4-Benzyloxy-3-trifluoromethylphenylamino)-pyrido[3,4-d]6-yl)-furan-2-carbaldehyde;-   5-((4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;-   5-((4-Benzyloxy-3-bromophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;-   5-((4-(3-Fluoro-benzyloxy-3-bromophenylamino)-pyrido[3,4-d]6-yl)-furan-2-carbaldehyde;-   5-((4-Benzyloxy-3-iodophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde;-   5-((4-(3-Fluoro-benzyloxy-3-iodophenylamino)-pyrido[3,4-d]6-yl)-furan-2-carbaldehyde;-   5-((4-Benzyloxy-3-fluorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carboxaldehyde;-   5-((4-(3-Fluoro-benzyloxy-3-fluorophenylamino)-pyrido[3,4-d]6-yl)-furan-2-carbaldehyde;-   N-[4-(benzyloxy)-3-chlorophenyl]-7-fluoro-6-chloro-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-chloro-4-quinazolinamine-   N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-chloro-4-quinazolinamine-   N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-chloro-4-quinazolinamine;-   N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-chloro-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-chloro-4-quinazolinamine;-   N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-chloro-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-chloro-4-quinazolinamine;-   N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-chloro-4-quinazolinamine;-   N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-chloro-4-quinazolinamine;-   N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-chloro-4-quinazolinamine;-   5-(4-[4-(Benzyloxy)-3-chlorophenylamino]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;-   5-(4-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;-   5-(4-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;-   5-(4-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;-   5-(4-[4-Benzyloxy-3-bromophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;-   5-(4-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;-   5-(4-[4-Benzyloxy-3-iodophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;-   5-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;-   5-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde-   5-(4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;-   5-(4-[1-(3-Fluorobenzyl-1H-indazol-5-ylamino]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;

EXAMPLES Example 1

(4-(4-Fluorobenzyloxy)-Phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-aminedihydrochloride

(4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(52 mg) in methanol (9 ml) and water (3 ml) was treated with Oxone™ (99mg) at room temperature for 2 days. The mixture was then partitionedbetween aqueous sodium carbonate solution and dichloromethane. The driedorganic phase was evaporated and the residue purified by Bond Elut™cartridge, followed by conversion to the hydrochloride salt, giving ayellow solid (31 mg); δH [²H₆]DMSO 9.9 (1H, bs) 9.25 (1H, s) 8.8 (1H, s)7.9 (2H, d) 7.5-7.6 (2H, m) 7.1-7.3 (5H, m) 6.9 (1H, d) 5.2 (2H, s) 4.5(2H, s) 3.6-3.8 (4H, m) 3.2 (3H, s); m/z 548 (M+1)⁺.

Example 2

(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-aminedihydrochloride

(4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(80 mg) in methanol (9 ml) and water (3 ml) was treated with Oxone™ (153mg) at room temperature for 2 days. The mixture was then partitionedbetween aqueous sodium carbonate solution and dichloromethane. The driedorganic phase was evaporated and the residue purified by Bond Elut™cartridge, followed by conversion to the hydrochloride salt, giving ayellow solid (69 mg); δH [²H₆]DMSO 9.8 (1H, bs) 9.4 (1H, s) 9.3 (1H, s)8.7 (1H, s) 7.8 (2H, d) 7.3-7.4 (2H, m) 7.0-7.3 (5H, m) 6.8 (1H, d) 5.3(2H, s) 4.4 (2H, s) 3.5-3.7 (4H, m) 3.1 (3H, s); m/z 548 (M+1)⁺.

Example 3

(4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-aminedihydrochloride

(4-Benzenesulphonyl-phenyl)-(6-(2-((2-methylthio-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine(162 mg) in methanol (20 ml) and water (10 ml) was treated with Oxone™(345 mg) at room temperature for 18 h. The mixture was then evaporatedand the residue purified by Bond Elut™ cartridge, followed by conversionto the hydrochloride salt, giving a yellow solid (55 mg); δH [²H₆]DMSO9.8 (1H, bs) 9.3 (1H, s) 9.2 (1H, s) 8.8 (1H, s) 8.3 (2H, d) 7.9-8.0(4H, m) 7.6-7.7 (3H, m) 7.2 (1H, d) 6.8 (1H, d) 4.4 (2H, s) 3.3-3.7 (4H,m) 3.1 (3H, s); m/z 564 (M+1)⁺.

Example 4

(4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-aminedihydrochloride

3-((4-(4-Benzyloxy-phenyl)-amino)-pyrido[3,4-d]pyrimidin-6-yl)-benzaldehyde(106 mg) and 2-methanesulphonyl-ethylamine (111 mg) in dichloromethane(5 ml) were reacted together as in Procedure D. Purification usingcolumn chromatography, followed by conversion to the hydrochloride salt,gave a yellow solid (66 mg); δH [²H₆]DMSO 9.6 (2H, bs) 9.3 (1H, s) 9.2(1H, s) 8.65 (1H, s) 8.55 (1H, s) 8.3 (1H, m) 7.7-7.8 (2H, m) 7.6 (2H,m) 7.25-7.45 (4H, m) 7.0 (2H, d) 5.1 (2H, s) 4.3 (2H, s) 3.2-3.8 (4H, m)3.1 (3H, s). m/z 540 (M+1)⁺.

Example 5

(4-Benzyloxyphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-aminedihydrochloride

(5-((4-(4-Benzyloxyphenyl)-amino)-quinazolin-6-yl)-furan-2-carbaldehyde(200 mg) and 2-methanesulphonyl-ethylamine (215 mg) in dichloromethane(10 ml) were reacted together as in Procedure D. Purification usingcolumn chromatography, followed by conversion to the hydrochloride salt,gave a yellow solid (121 mg); δH [²H₆]DMSO 9.7 (1H, s) 8.9 (1H, s) 8.4(1H, d) 8.0 (1H, d) 7.75 (2H, d) 7.3-7.5 (7H, m) 7.1 (2H, d) 6.85 (1H,d) 5.2 (2H, s) 4.4 (2H, s) 3.2-3.7 (4H, m) 3.1 (3H, s); m/z 529 (M+1)⁺.

Example 6

(4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-aminedihydrochloride

5-(4-(4-(3-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-furan-3-carbaldehyde(300 mg) and 2-methanesulphonyl-ethylamine (335 mg) in dichloromethane(15 ml) were reacted together as in Procedure D. Purification using aBond Elut™ cartridge, followed by conversion to the hydrochloride salt,gave a yellow solid (110 mg); δH [²H₆]DMSO 9.8 (2H, br) 9.3 (1H, s) 9.0(1H, s) 8.8 (1H, s) 8.2 (1H, s) 8.0 (1H, s) 7.1-7.8 (7H, m) 7.0 (1H, s)5.2 (2H, s) 4.1-4.3 (4H, brm) 3.3-3.5 (2H, bs) (hidden under H₂O peak)3.2 (3H, s); m/z 548 (M+1)⁺.

Example 7

(4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-quinazolin-4-yl)-aminedihydrochloride

4-(4-(4-Benzyloxy-phenyl)-amino)-quinazolin-6-yl)-thiazol-2-carbaldehyde(70 mg) and 2-methanesulphonyl-ethylamine (79 mg) in dichloromethane (10ml) were reacted together as in Procedure D. Purification using a BondElut™ cartridge, followed by conversion to the hydrochloride salt, gavea yellow solid (59 mg); δH [²H₆]DMSO 12.3 (1H, s) 10.0 (1H, s) 8.95 (1H,s) 8.8 (1H, s) 8.75 (1H, d) 7.4-7.6 (6H, m) 7.2 (2H, d) 5.25 (2H, s) 4.8(2H, s) 3.6-3.8 (4H, m) 3.2 (3H, s); m/z 546 (M+1)⁺.

Example 8

N-{4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-{4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 9.40 (s, 1H); 8.67 (s, 1H); 8.30 (d, 1H); 7.86 (d, 1H); 7.75(d, 2H); 7.43 (m, 1H); 7.30-7.21 (m, 3H); 7.15 (m, 1H); 7.07 (d, 2H);6.80 (d, 1H); 5.15 (s, 2H); 4.40 (s, 2H); 3.65 (m, 2H); 3.40 (m, 2H);3.11 (s, 3H); MS m/z 547 (M+1).

Example 9

N-{4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-{3-methoxy-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 9.22 (s, 1H); 8.78 (s, 1H); 8.31 (d, 1H); 7.88 (d, 1H);7.50-7.08 (m, 8H); 6.84 (d, 1H); 5.13 (s, 2H); 4.42 (s, 2H); 3.80 (s,3H); 3.60 (m, 2H); 3.40 (m, 2H, obscured by water peak); 3.10 (s, 3H);MS m/z 577 (M+1).

Example 10

N-[4-(benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared in a similar manner to Procedure D from5-(4-(4-benzyloxy-phenylamino)-7-methoxy-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride (78 mg, 0.16 mmol), 2-methanesulphonylethylamine (33 mg,0.27 mmol), acetic acid (15 mg, 0.25 mmol) and triethylamine (18 mg,0.18 mmol) in 3 ml of 1,2-dichloroethane added to sodiumtriacetoxyborohydride (102 mg, 0.48 mmol) portionwise over a two dayperiod. The reaction mixture was stirred four days and then partitionedbetween 10 ml of 0.5M NaHCO₃ solution and 50 ml of ethyl acetate. Theorganic solution was dried with Na₂SO₄ and concentrated in vacuo. Theresidue was chromatographed on silica gel with methanol/methylenechloride (1:49 to 2:48). The resulting solid was crystallized from asmall volume of ethyl acetate, suspended in ether and filtered to give43 mg of product as a pale yellow solid. δ¹H NMR (400 MHz, DMSO-d₆) 9.78(s, 1H), 8.73 (s, 1H), 8.42 (s, 1H), 6.64 (d, 2H), 7.47 (m, 2H), 7.40(m, 2H), 7.33 (m, 1H), 7.25 (s, 1H), 7.04 (d, 2H), 6.98 (d, 1H), 6.46(d, 1H), 5.12 (s, 2H), 4.04 (s, 3H), 3.86 (s, 2H), 3.28 (t, 2H), 3.01(s, 3H), 2.99 (t, 2H). ESI-MS m/z 559 (M+1).

Example 11

N-[4-(benzyloxy)phenyl]-6-[4-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-{4-benzyloxyanilino}-6-quinazolinyl)-furan-3-carbaldehyde (0.6equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz,d6DMSO 9.51 (bs, 2H), 9.11 (s, 1H), 8.79 (s, 1H), 8.29 (d, 1H), 8.06 (s,1H), 7.90 (d, 1H), 7.60 (d, 2H), 7.5-7.3 (m, 5H), 7.11 (d, 2H), 5.14 (s,2H), 4.14 (bs, 2H), 3.6-3.5 (m, 3H), 3.12 (s, 3H); MS m/z 529 (M+1).

Example 12

N-{4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

Prepared according to Procedure F from6-iodo-(4-(3-fluorobenzyloxy)-3-methoxypheny)quinazolin-4-ylamine (1equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1equiv) andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv). ¹H NMR 400 MHz (CD₃OD) 9.40 (s, 1H); 8.79 (s, 1H); 8.76 (d, 1H);8.38 (s, 1H); 7.89 (d, 1H); 7.50 (s, 1H); 7.40 (t, 1H); 7.34 (m, 1H);7.27 (d, 1H); 7.22 (d, 1H); 7.08 (d, 1H); 7.03 (t, 1H); 5.19 (s, 2H);4.81 (s, 2H); 3.85 (m, 2H); 3.75 (m, 2H); 3.10 (s, 3H); MS m/z 594(M+1)⁺, 592 (m−1)⁻.

Example 13

N-{4-[(3-bromobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

Prepared according to Procedure F from6-iodo-(4-(3-bromobenzyloxy)-phenyl)quinazolin-4-ylamine (1 equiv),2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv)and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide(1 equiv). ¹H NMR 400 MHz (CD₃OD) 9.40 (s, 1H); 8.78 (d, 1H); 8.74 (d,1H); 8.34 (s, 1H); 7.88 (d, 1H); 7.65 (d, 2H); 7.62 (s, 1H); 7.48 (d,1H); 7.30 (d, 1H); 7.30 (m, 1H); 7.12 (d, 2H); 5.16 (s, 2H); 4.80 (s,2H); 3.85 (m, 2H); 3.75 (m, 2H); 3.10 (s, 3H); MS m/z 624, 626 (M+1)⁺,622, 624 (m−1)⁻.

Example 14

N-{4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

Prepared according to Procedure F from6-iodo-(4-(3-fluorobenzyloxy)-phenyl)-quinazolin-4-ylamine and (1equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1equiv) andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv). ¹H NMR 400 MHz (CD₃OD) 9.44 (s, 1H); 8.79 (s, 1H); 8.76 (d, 1H);8.37 (s, 1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.53 (d, 1H); 7.46 (d, 2H);7.38 (m, 2H); 7.32 (d, 1H); 7.24 (d, 1H); 5.21 (s, 2H); 4.82 (s, 2H);3.85 (m, 2H); 3.77 (m, 2H); 3.11 (s, 3H); MS m/z 564 (M+1)⁺, 562 (m−1)⁻.

Example 15

N-[4-(benzyloxy)-3-fluorophenyl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

Prepared according to Procedure F from6-iodo-(4-benzyloxy)-3-fluorophenyl)quinazolin-4-ylamine andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1equiv) andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv). ¹H NMR 400 MHz (CD₃OD) 9.41 (s, 1H); 8.77 (d, 1H); 8.75 (s, 1H);8.36 (s, 1H); 7.90 (d, 1H); 7.71 (d, 2H); 7.60 (m, 1H); 7.40 (m, 1H);7.23 (m, 1H); 7.11 (d, 2H); 7.03 (m, 1H); 5.17 (s, 2H); 4.81 (s, 2H);3.85 (m, 2H); 3.76 (m, 2H); 3.10 (s, 3H); MS m/z 564 (M+1)⁺, 562 (m−1)⁻.

Example 16

N-(1-benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-{4-(1-benzyl-1H-indazol-5-yl)-7-methoxy-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). δ ¹H NMR (400MHz, DMSO-d₆) 9.94 (s, 1H), 8.76 (s, 1H), 8.43 (s, 1H), 8.13 (d, 1H),8.12 (s, 1H), 7.70 (d, 1H), 7.66 (m, 1H), 7.31 (m, 2H), 7.25 (m, 4H),7.00 (d, 1H), 6.46 (d, 1H), 5.67 (s, 2H), 4.05 (s, 3H), 3.85 (s, 2H),3.27 (t, 2H), 3.00 (s, 3H), 2.98 (t, 2H); ESI-MS m/z 583 (M+1).

Example 17

6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine

Prepared according to Procedure D from5-(4-{4-(3-trifluoromethylbenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 300 MHz(DMSO-d6) 11.63 (bs, 1H); 9.88 (bs, 1H); 9.59 (bs, 1H); 8.88 (s, 1H);8.43 (d, 1H); 7.97 (d, 1H); 7.90-7.67 (m, δH); 7.34 (d, 1H); 7.19 (d,2H); 6.89 (d, 1H); 5.30 (s, 2H); 4.45 (s, 2H); 3.78 (m, 2H); 3.45 (m,2H, obscured by water peak); 3.19 (s, 3H); MS m/z 597 (M+1).

Example 18

N-{3-fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-{3-fluoro-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 9.61 (bs, 2H); 9.28 (bs, 1H); 8.80 (s, 1H); 8.34 (d, 1H); 7.87(m, 2H); 7.59 (d, 1H); 7.44 (m, 1H); 7.2-7.38 (m, 4H); 7.18 (m, 1H);6.83 (s, 1H); 5.25 (s, 2H); 4.42 (s, 2H); 3.60 (m, 2H); 3.45 (m, 2H,obscured by water peak); 3.16 (s, 3H); MS m/z 565 (M+1).

Example 19

N-{4-[(3-bromobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-{3-bromo-4-benzyloxyanilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 11.78 (bs, 1H); 9.65 (bs, 1H); 9.39 (bs, 1H); 8.78 (s, 1H);8.37 (d, 1H); 7.90 (d, 1H); 7.66 (m, 3H); 7.53 (d, 1H); 7.42 (d, 1H);7.38 (m, 1H); 7.22 (s, 1H); 7.18 (d, 2); 6.82 (d, 1H); 5.18 (s, 2H);4.41 (s, 2H); 3.62 (m, 2H); 3.44 (m, 2H, obscured by water peak); 3.10(s, 3H); MS m/z 606, 608 (M+1).

Example 20

N-[4-(benzyloxy)phenyl]-6-[3-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-(4-benzyloxyanilino)-6-quinazolinyl)-furan-2-carbaldehyde (0.6equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹HNMR 400 MHz,(d6DMSO) 9.46 (brs, 1H), 8.94 (s, 1H), 8.7 (s, 1H), 8.16 (d, 1H), 7.96(s, 1H), 7.88 (d, 1H), 7.67 (d, 2H), 7.5-7.2 (m, 5H), 7.07 (d, 2H), 6.93(s, 1H), 5.12 (s, 2H), 4.38 (brs, 2H), 3.59 (m, 2H), 3.46 (brs, 2H),3.09 (s, 3H); MS m/z 529 (M+1)

Example 21

N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

Prepared according to Procedure F from6-iodo-(4-(3-fluorobenzyl)-1H-indazol-5-yl)quinazolin-4-ylamine (1equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1equiv) andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv). ¹H NMR (d₄ MeOH) d 9.44 (s, 1H), 8.76 (m, 2H), 8.36 (s, 1H),8.18 (s, 1H), 8.15, (s, 1H), 7.92 (d, 1H), 7.75 (m, 2H), 7.34 (m, 1H),7.04 (m, 2H), 6.92 (d, 1H), 5.71 (s, 2H), 4.80 (s, 2H), 3.82 (m, 2H),3.74 (m, 2H), 3.08 (s, 3H); MS m/z 588 (M+H⁺)

Example 22

6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-{4-(benzenesulphonyl)phenyl}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR(DMSO-d6) 10.27 (s, 1H), 8.78 (s, 1H), 8.65 (s, 1H), 8.18-8.22 (m, 3H),7.97-8.01 (m, 4H), 7.86 (d, 1H), 7.62-7.72 (m, 3H), 7.10 (d, 1H), 6.51(d, 1H), 3.84 (s, 1H), 3.28 (t, 2H), 3.03 (s, 3H), 2.99 (t, 2H); m/z(M+1)⁺ 563.

Example 23

6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine

Prepared according to Procedure F from6-iodo-(4-(benzenesulphonyl)-phenyl)-quinazolin-4-ylamine (1 equiv),2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv)and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide(1 equiv). ¹H NMR 400 MHz (DMSO-d6) 9.80 (s, 1H); 8.87 (s, 1H); 8.65 (s,1H); 8.64 (s, 1H); 8.17 (s, 1H); 8.03 (s, 1H); 7.98 (m, 2H); 7.66 (m,5H); 4.73 (s, 2H); 3.68 (m, 2H); 3.55 (m, 2H); 3.12 (s, 3H); MS m/z 580(M+1)⁺, 578 (m−1)⁻.

Example 24

6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine

Prepared according to Procedure F from6-iodo-(4-(3-trifluoromethylbenzyloxy)-phenyl)quinazolin-4-ylamine (1equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1equiv) andN-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1equiv). ¹H NMR 400 MHz (CD₃OD) 9.40 (s, 1H); 8.75 (d, 1H); 8.73 (s, 1H);8.35 (s, 1H); 7.89 (d, 1H); 7.77 (s, 1H); 7.73 (m, 1H); 7.61 (m, 3H);7.52 (m, 1H); 7.14 (d, 2H); 5.24 (s, 2H); 4.82 (s, 2H); 3.85 (m, 2H);3.76 (m, 2H); 3.10 (s, 3H); MS m/z 614 (M+1)⁺, 612 (m−1)⁻.

Example 25

N-{3-fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

Prepared according to Procedure F from6-iodo-4-(1-benzyl-1H-indazol-5-yl)-quinazolin-4-ylamine (1 equiv),2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv)and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide(1 equiv). ¹H NMR 400 MHz (CD₃OD) 9.28 (s, 1H); 8.78 (s, 1H); 8.74 (d,1H); 8.31 (s, 1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.63 (m, 1H); 7.54 (m,1H); 7.49 (m, 1H); 7.37 (m, 1H); 7.25 (m, 2H); 7.05 (m, 1H); 5.24 (s,2H); 4.77 (s, 2H); 3.81 (m, 2H); 3.72 (m, 2H); 3.10 (s, 3H); MS m/z 582(M+1)⁺, 580 (m−1)⁻

Example 26

N-(1-benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine

Prepared according to Procedure F from6-iodo-4-(1-benzyl-1H-indazol-5-yl)-quinazolin-4-ylamine (1 equiv),2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv)and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide(1 equiv). δ¹H NMR (d₄ MeOH) 9.37 (s, 1H), 8.74 (m, 2H), 8.33 (s, 1H),8.17 (s, 1H), 8.14, (s, 1H), 7.90 (d, 1H), 7.70 (m, 2H), 7.22 (m, 5H),5.69 (s, 2H), 4.78 (s, 2H), 3.81 (m, 2H), 3.74 (m, 2H), 3.09 (s, 3H); MSm/z 570 (M+H⁺).

Example 27

N-(3-Fluoro-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-{3-fluoro-4-benzyloxyanilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 8.83 (s, 1H); 8.35 (d, 1H); 7.89 (d, 1H); 7.83 (d, 1H); 7.59(d, 1H); 7.48-7.31 (m, 7H); 7.26 (s, 1H); 6.83 (d, 1H); 5.21 (s, 2H);4.42 (s, 2H); 3.60 (m, 2H); 3.44 (m, 2H, obscured by water peak); 3.12(s, 3H); MS m/z 547 (M+H⁺).

Example 28

N-(3-Chloro-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-{3-chloro-4-benzyloxyanilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 9.71 (bs, 2H); 9.45 (bs, 1H); 8.86 (s, 1H); 8.36 (d, 1H); 7.98(d, 1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.49-7.44 (m, 2H); 7.40 (m, 2H);7.35-7.30 (m, 2H); 7.28 (d, 1H); 6.83 (d, 1H); 5.25 (s, 2H); 4.42 (s,2H); 3.62 (m, 2H); 3.44 (m, 2H); 3.12 (s, 3H); MS m/z 563 (M+H⁺).

Example 29

N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR 400 MHz(DMSO-d6) 9.60 (bs, 1H); 9.32 (bs, 1H); 8.82 (bs, 1H); 8.34 (d, 1H); 8.0(s, 1H); 7.88 (d, 1H); 7.74 (d, 1H); 7.45 (m, 1H); 7.34-7.23 (m, 4H);7.17 (m, 1H); 6.83 (d, 1H); 5.27 (s, 2H); 4.42 (s, 2H); 3.59 (m, 2H);3.40 (m, 2H, obscured by waterpeak); 3.12 (s, 3H); MS m/z 581 (M+H⁺).

Example 30

(4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazol-4-yl)-quinolin-4-yl)amine

A suspension of(4-(4-(4-phenoxy)anilino)-quinolin-7-yl)thiazole-2-carbaldehyde (0.05 g,0.14 mmol), sodium triacetoxyborohydride (0.12 g, 0.56 mmol),methanesulphonylethylamine (0.15 g, 1.2 mmol) and powdered 3 Å molecularsieves in dichloromethane (6 ml) and glacial acetic acid (1 ml) wasstirred at room temperature (21° C.) overnight (18 hrs) according toProcedure D. The crude reaction mixture was filtered through a SPEcolumn (SCX resin, 5 g, 25 ml), sequentially washed with methanol (2×10ml) and 10% ammonia in methanol (3×10 ml) and the product isolated as apale yellow gum. Trituration with water (5 ml) and drying of theresultant solid over phosphorus pentoxide at 60° C. under vacuum for 5hrs yielded the purified product as a pale yellow solid (0.031 g, 49%);δH [²H₆] DMSO 8.80 (1H, s), 8.25 (3H, m), 8.10 (1H, s), 7.90 (1H, d),7.20 (4H, 2d), 6.85 (5H, m), 6.60 (1H, d), 3.95 (2H, d), 2.90 (7H, m);m/z 531 (M+1)⁺.

Example 31

(4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazol-5-yl)-quinolin-4-yl)amine

4-(4-Phenoxyanilino) 7-(4-formyl thiazol-5-yl) quinoline (50 mg, 0.118mmol), methanesulphonylethylamine (50 mg) and molecular seives (4A, 2large spatula tips) were stirred in a mixture of dichloromethane (6 ml)and acetic acid (1 ml) at room temperature for 2 hr (Procedure D).Sodium triacetoxyborohydride (0.12 g, 0.567 mmol) was then added and thereaction was stirred at room temp for 18 hr. The reaction mixture wasadded to a 5 g SCX cartridge and washed with methanol, the product waseluted with 10% methanolic ammonia. The product was triturated withwater to give a beige solid (39.7 mg); δH [²H₆] DMSO 9.32 (1H, s), 9.22(1H, s), 8.64 (2H, m), 8.19 (1H, s), 7.87 (1H, d), 7.56 (4H, m), 7.27(6H, m), 7.02 (1H, d), 4.07 (2H, s), 3.42 (2H, t), 3.14 (5H, m); m/z531.

Example 32

(4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-2-yl)-quinolin-4-yl)amine

5-(4-(4-phenoxyphenylamino)-quinolin-7-yl)furan-2-carbaldehyde (0.05 g)was reacted with 2-(methanesulphonyl)ethylamine (0.075 g) according toprocedure D. Acidification with acetic acid (0.5 ml) followed bypurification using a ion-exchange (SCX) Bond Elut™ cartridge, elutingwith methanol-ammonia (9:1), concentration and trituration withdiethylether afforded an off-white solid; δH [²H₆] DMSO 8.44 (1H, d),8.41 (1H, d), 8.11 (1H, s), 7.85 (1H, d), 7.44-7.35 (4H, m), 7.18-7.03(6H, m), 6.79 (1H, d), 6.47 (1H, d), 3.82 (2H, s), 3.01 (2H, t); m/z 514(M+1)⁺.

Example 33

6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-7-methoxy-N-(4-benzenesulphonyl)phenyl-4-quinazolinamine

Prepared according to Procedure D from5-(7-methoxy-4-(4-benzenesulphonyl)phenylamino-quinazolin-6-yl)furan-2-carbaldehydehydrochloride (0.6 equiv) and 2-methanesulphonyl (1 equiv). δ¹H NMR (400MHz, DMSO-d₆) 10.23 (s, 1H), 8.76 (s, 1H), 8.59 (s, 1H), 8.14 (d, 2H),7.96 (m, 4H), 7.59-7.71 (m, 3H), 7.33 (s, 1H), 7.03 (d, 1H), 6.47 (d,1H), 4.06 (s, 3H), 3.86 (s, 2H), 3.27 (t, 2H), 3.00 (s, 3H), 2.98 (t,2H). ESI-MS m/z 593 (M+1).

Example 34

N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D from a mixture of5-(4-(4-benzyloxy-phenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehydehydrochloride (0.13 grams) in 1,2-dichloroethane (3 ml),diisopropylethylamine (65 mg), acetic acid (45 mg),2-methanesulphonylethylamine (0.125 grams), and sodiumtriacetoxyborohydride (0.27 grams). The mixture was stirred for 18hours. The reaction mixture was quenched with methanol (3 ml) and pouredinto a separatory funnel containing aqueous saturated sodium hydrogencarbonate (100 ml) and ethyl acetate (100 ml). The mixture wasextracted. The organic layer was washed with water. The organic layerwas dried over magnesium sulfate, filtered, and concentrated. Theresidue was treated with ethyl acetate/hexanes and collected byfiltration (0.083 g, 61% yield). δ¹H NMR (400 MHz, DMSO-d₆) 9.98 (s,1H), 8.83 (d, 1H), 8.44 (s, 1H), 7.58 (m, 3H), 7.44 (m, 2H), 7.37 (m,2H), 7.31 (m, 1H), 7.03 (d, 1H), 6.91 (m, 1H), 6.5 (d, 1H), 5.1 (s, 2H),3.84 (s, 1H), 3.25 (m, 2H), 2.99 (s, 3H), 2.96 (m, 2H). ESI-MS m/z 545(M−1).

Example 35

N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-(1-Benzyl-1H-indazol-5-ylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). δ ¹H NMR (400MHz, DMSO-d₆) 10.16 (s, 1H), 8.91 (d, 1H), 8.46 (s, 1H), 8.11 (s, 2H),7.65 (m, 3H), 7.26 (m, 5H), 6.93 (m, 1H), 6.54 (d, 2H), 5.65 (s, 2H),3.89 (s, 2H), 3.28 (m, 2H), 2.99 (m, 5H). ESI-MS m/z 569 (M−1).

Example 36

N-[4-(Phenylsulphonyl)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D from5-(4-(4-Phenylsulphonylphenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde(0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). ¹H NMR (400MHz, DMSO-d₆) δ: 10.38 (s, 1H), 8.87 (d, 1H), 8.62 (s, 1H), 8.11 (d,2H), 7.95 (m, 4H), 7.63 (m, 4H), 6.94 (m, 1H), 6.51 (d, 1H), 3.84 (s,2H), 3.25 (m, 2H), 2.98 (s, 3H), 2.95 (m, 2H). ESI-MS m/z 579 (M−1).

Example 37

N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine

The mixture of5-(4-(4-benzyloxy-3-trifluoromethylphenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde(211 mg, 0.40 mmol), 2-methanesulphonyl-ethylamine (99 mg, 2.0 mmol),acetic acid (0.5 ml) in dichloromethane (15 ml) was stirred at roomtemperature for 1.5 hours then was heated to reflux for 1 hour. Themixture was cooled to 0° C. with ice bath. Sodium cyanoborohydride (50mg, 0.8 mmol) was added at 0° C. The reaction mixture then was stirredat room temperature for 1 hour. Diluted with ethyl acetate (50 ml), thenquenched with saturated sodium bicarbonate solution slowly. Extractedwith ethyl acetate and the combined organic extracts were washed withbrine, dried over MgSO₄ and concentrated in vacuo. Purification of theresulting residue was accomplished using flash chromatography on silicagel with 2% methanol in ethyl acetate which afforded a yellow solid(0.10 g, 43% yield). H¹ NMR (400 MHz, DMSO). δ10.0 (s, 1H), 8.7 (s, 1H),8.5 (s, 1H), 8.1 (d, 1H), 8.1 (s, 2H), 7.8 (d, 1H), 7.4 (m, 5H), 7.3 (m,1H), 7.0 (d, 1H), 6.5 (d, 1H), 5.3 (s, 2H), 3.8 (s, 2H), 3.2 (m, 2H),3.0 (s, 3H), 2.9 (m, 2H). ESI-MS m/z 597 (M+H)⁺.

Further Examples

The compounds in Lists 1 to 48 above and their hydrochloride salts, ifappropriate, are prepared by analogous techniques using the appropriatestarting materials.

Biological Data

Compounds of the present invention were tested for protein tyrosinekinase inhibitory activity in substrate phosphorylation assays and cellproliferation assays.

Substrate Phosphorylation Assay

The substrate phosphorylation assays use baculovirus expressed,recombinant constructs of the intracellular domains of c-erbB-2 andc-erbB-4 that are constitutively active and EGFr isolated fromsolubilised A431 cell membranes. The method measures the ability of theisolated enzymes to catalyse the transfer of the g-phosphate from ATPonto tyrosine residues in a biotinylated synthetic peptide(Biotin-GluGluGluGluTyrPheGluLeuVal). Substrate phosphorylation wasdetected following either of the following two procedures: a.) c-ErbB-2,c-ErbB4 or EGFr were incubated for 30 minutes, at room temperature, with10 mM MnCl₂, 10 mM ATP, 5 mM peptide, and test compound (diluted from a5 mM stock in DMSO, final DMSO concentration is 2%) in 40 mM HEPESbuffer, pH 7.4. The reaction was stopped by the addition of EDTA (finalconcentration 0.15 mM) and a sample was transferred to astreptavidin-coated 96-well plate. The plate was washed and the level ofphosphotyrosine on the peptide was determined using a Europium-labelledantiphosphotyrosine antibody and quantified with a time-resolvedfluorescence technique. b.) ErbB2 was incubated for 50 minutes at roomtemperature with 15 mM MnCl2, 2 mM ATP, 0.25 mCi [γ-³³P] ATP/well, 5 mMpeptide substrate, and test compound (diluted from a 10 mM stock inDMSO, final DMSO concentration is 2%) in 50 mM MOPS pH 7.2. The reactionwas terminated by the addition of 200 ml of PBS containing 2.5 mg/mlstreptavidin-coated SPA beads (Amersham Inc.), 50 mM ATP, 10 mM EDTA and0.1% TX-100. The microtitre plates were sealed and SPA beads wereallowed to settle for at least six hours. The SPA signal was measuredusing a Packard Topcount 96-well plate scintillation counter (PackardInstrument Co., Meriden, Conn.).

The results are shown in Tables 1A (examples 1 to 7) and 1B (examples 8to 29 and 33 to 37) as the IC₅₀ values.

TABLE 1A Substrate Phosphorylation Example erbB2 - assay (b) EGF-r -assay (a) 1 +++ +++ 2 +++ +++ 3 +++ +++ 4 ++ +++ 5 +++ +++ 6 ++ 7 ++++++

TABLE 1B Substrate Phosphorylation Example erbB2 - assay (b) 8 +++ 9 +++10 +++ 11 +++ 12 ++ 13 ++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++ 19 +++ 20+++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++ 33+++ 34 +++ 35 +++ 36 +++ 37 +++ IC₅₀ values Symbol <0.10 μM +++ 0.10-1.0μM ++ 1.0-10.0 μM + >10.0 μM − Not determined NDCellular Assays: Methylene Blue Growth Inhibition Assay

Human breast (BT474), head and neck (HN5) and gastric tumor (N87) celllines were cultured in low glucose DMEM (Life Technologies 12320-032)containing 10% fetal bovine serum (FBS) at 37° C. in a humidified 10%CO₂, 90% air incubator. The SV40 transformed human mammary epithelialcell line HB4a was transfected with either human H-ras cDNA (HB4a r4.2)or the human c-erbB2 cDNA (HB4a c5.2). The HB4a clones were cultured inRPMI containing 10% FBS, insulin (5 μg/ml), hydrocortisone (5 μg/ml),supplemented with the selection agent hygromycin B (50 μg/ml). Cellswere harvested using trypsin/EDTA, counted using a haemocytometer, andplated in 100 ml of the appropriate media, at the following densities,in a 96-well tissue culture plate (Falcon 3075): BT474 10,000cells/well, HN5 3,000 cells/well, N87 10,000 cells/well, HB4a c5.2 3,000cells/well, HB4a r4.2 3,000 cells/well. The next day, compounds werediluted in DMEM containing 100 mg/ml gentamicin, at twice the finalrequired concentration, from 10 mM stock solutions in DMSO. 100 ml/wellof these dilutions were added to the 100 ml of media currently on thecell plates. Medium containing 0.6% DMSO was added to control wells.Compounds diluted in DMEM were added to all cell lines, including theHB4a r4.2 and HB4a c5.2 cell lines. The final concentration of DMSO inall wells was 0.3%. Cells were incubated at 37° C., 10% CO₂ for 3 days.Medium was removed by aspiration. Cell biomass was estimated by stainingcells with 1000 per well methylene blue (Sigma M9140, 0.5% in 50:50ethanol:water), and incubation at room temperature for at least 30minutes. Stain was removed, and the plates rinsed under a gentle streamof water, and air-dried. To release stain from the cells 1000 ofsolubilization solution was added (1% N-lauroyl sarcosine, Sodium salt,Sigma L5125, in PBS), and plates were shaken gently for about 30minutes. Optical density at 620 nM was measured on a microplate reader.Percent inhibition of cell growth was calculated relative to vehicletreated control wells. Concentration of compound that inhibits 50% ofcell growth (IC₅₀) was interpolated using nonlinear regression(Levenberg-Marquardt) and the equation, y=V_(max)*(1−(x(K+x)))+Y2, where“K” was equal to the IC₅₀.

Table 2 illustrates the inhibitory activity of compounds of the presentinvention as IC₅₀ values in μM against a range of tumor cell lines.

TABLE 2 Cell Proliferation HB4a HB4a Example erbB2 ras BT474 HN5 N87 1+++ + +++ +++ +++ 2 +++ + +++ +++ +++ 3 +++ + +++ +++ +++ 4 +++ − ++++++ +++ 5 +++ − +++ +++ +++ 6 +++ + +++ +++ +++ 7 +++ ++ +++ +++ +++ 8+++ ++ +++ +++ +++ 9 +++ ++ +++ +++ +++ 10 +++ ++ +++ +++ +++ 11 +++ −+++ +++ +++ 12 +++ − +++ ++ +++ 13 ++ − ++ + ++ 14 +++ − +++ +++ +++ 15+++ − +++ +++ +++ 16 +++ ++ +++ +++ +++ 17 ++ ++ +++ ++ ++ 18 +++ ++ ++++++ +++ 19 +++ − +++ +++ +++ 20 +++ − +++ ++ +++ 21 +++ ++ +++ +++ +++22 +++ + +++ +++ +++ 23 +++ + +++ +++ +++ 24 ++ − ++ +++ ++ 25 +++ − ++++++ +++ 26 +++ ++ +++ +++ +++ 27 +++ ++ +++ +++ +++ 28 +++ + +++ +++ +++29 +++ − +++ +++ +++ 33 +++ +++ +++ +++ +++ 34 +++ − +++ +++ +++ 35+++ + +++ +++ +++ 36 ++ − ++ ++ ++ 37 +++ + +++ +++ +++ IC₅₀ valueSymbol <5 μM +++ 5-25 μM ++ 25-50 μM + >50 μM − Not determined NDMajor Metabolites:

Liver S-9 homogenates (5 mg/mL protein concentration) from preparedpooled male Sprague Dawley rat livers and pooled human livers (XenoTech,LLC, Kansas City, Kans.) were incubated in 96-well polypropylene plateswith representative examples selected from examples 1 to 40 (10 μM) in atotal volume of 0.5 mL. Stock solutions of these compounds were preparedin DMSO at a concentration of 1 mM to maintain a <1% final DMSOconcentration for each reaction. Enzymatic incubations containedcofactors (5.71 mM NADPH, 7.14 mM glucose-6-phosphate, 7.14 mM UDPGA,47.1 mM potassium chloride, and 11.4 mM magnesium chloride in 0.1 Mpotassium phosphate buffer, pH 7.4). Control samples were aspirated fromthe reaction samples at time zero and placed immediately into 2 volumesof ice-chilled acetonitrile. Sample reaction plates were incubated for60 min in a shaker incubator maintained at 37° C. supplied with O₂.Reactions were terminated by addition of 2 volumes of ice-chilledacetonitrile. All samples were vortexed and centrifuged at 2000×g for 10min. The supernatant was removed and analyzed by LC-MS. The metaboliteidentification work was done by using reversed-phase HPLC coupled withion-trap mass spectroscopy.

For example:

N-[4-(Benzyloxy)phenyl]-6-[4-(aminomethyl)-2-furyl]-4-quinazolinamine

Prepared according to Procedure D and identified as a major metaboliteofN-[4-(benzyloxy)phenyl]-6-[4-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinaminein ¹HNMR 300 MHz, CDCl3 8.69 (s, 1H), 8.11 (s, 1H), 8.02 (d, 1H), 7.88(d, 1H), 7.61 (d, 2H), 7.5-7.2 (m, 7H), 7.05 (d, 2H), 6.83 (s, 1H), 5.10(s, 2H), 3.82 (s, 2H); MS m/z 423 (M+1).

Thus, particular compounds of interest as metabolites (either asisolated compounds or compounds in vivo) are compounds of formula(XVII):

in which Ar, Y, V, X and U are as defined above; all possiblepreferments for these groups as defined above are applicable.

Compounds of formula (XII) of special interest include:

-   4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzenesulphonyl-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(3-(aminomethyl)phenyl-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-quinazolin-4-yl)-amine;-   (4-(3-Fluorobenzyloxy-phenyl)-(6-(4-(aminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;-   (4-Benzyloxy-phenyl)-(6-(2-(aminomethyl)-thiazol-4-yl)-quinazolin-4-yl)-amine;-   N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;-   N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;-   N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;-   N-[4-(Benzyloxy)phenyl]-6-[4-(aminomethyl)-2-furyl]-4-quinazolinamine;-   N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-[4-(Benzyloxy)-3-fluorophenyl]-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;-   6-[5-(aminomethyl)-2-furyl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine;-   N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;-   N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;-   N-[4-(Benzyloxy)phenyl]-6-[3-(aminomethyl)-2-furyl]-4-quinazolinamine;-   N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   6-[5-(Aminomethyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine;-   6-[2-(Aminomethyl)-1,3-thiazol-4-yl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine;-   6-[2-(Aminomethyl)-1,3-thiazol-4-yl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine-   N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-(1-Benzyl-1H-indazol-5-yl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-(3-Fluoro-4-benzyloxyphenyl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-(3-Chloro-4-benzyloxyphenyl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine;-   N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;-   (4-Phenoxyphenyl)-(7-(2-(aminomethyl)-thiazol-4-yl)-quinolin-4-yl)amine;-   (4-Phenoxyphenyl)-(7-(4-(aminomethyl)-thiazol-5-yl)-quinolin-4-yl)amine;-   (4-Phenoxyphenyl)-(7-(5-(aminomethyl)-furan-2-yl)-quinolin-4-yl)amine;-   6-[5-(Aminomethyl)-2-furyl]-7-methoxy-N-(4-phenylsulphonyl)phenyl-4-quinazolinamine;-   N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;-   N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;-   N-[4-(Benzenesulphonyl)phenyl]-7-fluoro-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine;-   N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-(aminomethyl)-4-furyl]-4-quinazolinamine;    and salts or solvates thereof, particularly pharmaceutically    acceptable salts thereof.

The invention claimed is:
 1. A method of treating breast cancer byadministering a pharmaceutical formulation presented in unit dose formcomprising the compound of formula

as an active ingredient, wherein said active ingredient is presentwithin said unit dose form in an amount from 0.5 mg to 1 g.
 2. Themethod of claim 1, wherein the pharmaceutical formulation isadministered as a single dose per day.
 3. The method of claim 1, whereinthe pharmaceutical formulation is administered as a number of sub-dosesper day.
 4. The method of claim 1, wherein said unit dose is a tablet.